Amide compounds and use of the same

ABSTRACT

An amide compound of the formula (I):
 
                 
 
 
 
wherein R is amino and the like, A is alkylene and the like, X is O, S and the like, M is arylene and the like, R 1 , R 2 , R 3  and R 4  are H, hydroxy and the like, R 5  is H, alkyl and the like, m is an integer of 0-6, R 6  is an optionally substituted aryl and the like, and R 7  is H, an optionally substituted alkyl and the like, a pharmaceutically acceptable acid addition salt thereof and a pharmaceutical containing same as an active ingredient. The amide compounds exhibit superior suppressive effects on cytokines directly or indirectly involved in inflammations, such as IL-8, IL-1, IL-6, TNF-α, GM-CSF and the like, and are useful for the prophylaxis and treatment of rheumatic diseases, arthritis due to gout and the like.

This application is a Reissue application of U.S. Ser. No. 09/011,983,filed Feb. 20, 1998, now U.S. Pat. No. 6,174,887, granted Jan. 16, 2001,which is a § 371 of PCT/JP96/02305, filed Aug. 15, 1996.

TECHNICAL FIELD

The present invention relates to a novel compound exhibiting superiorsuppressive effects on cytokines directly or indirectly involved ininflammations, such as interleukin-8 (IL-8), interleukin-1 (IL-1),interleukin-6 (IL-6), tumor necrosis factor (TNF-α), GM-CSF and thelike, and pharmaceutical agents comprising said compound, such asanti-inflammatory agents.

BACKGROUND ART

An inflammation is one of the protective responses in the livingorganisms which aims at removal of foreign substances, pathogenicbacteria and so on, as well as repair of damaged tissues. Wheninflammatory stimulation is received, the microcirculatory systemresponds and particularly increases vascular permeability. The vascularpermeability is promoted by chemical mediators and cytokines.Sequentially, chemotaxis, migration and activation of neutrophiles areinduced, foreign substances and pathogenic bacteria are phagocytosed atthe sites of inflammation, and chemical mediators are released to induceinflammatory responses. Subsequent to neutrophiles, chemotaxis andrecruitment of macrophages at the local sites occur, and activatedmacrophages, like neutrophiles, phagocytose foreign substances,pathogenic bacteria, disintegrated tissues and so on to produce variouscytokines. Then, pathogenic bacteria, foreign substances and damagedtissues are removed and the tissues are reconstructed, whereby theinflammation comes to an end. The above-mentioned process occurs innormal inflammatory responses. In allergy and autoimmune diseases suchas rheumatoid arthritis and systemic lupus erythematosus, however,abnormal immune responses prolong inflammation and cause strong systemicsymptoms.

Many cytokines are involved in various processes of inflammatoryresponses. For example, IL-1, TNF-α and IL-8 are responsible for thechemotaxis, adhesion to vascular endothelial cells, and migration intovascular walls, of leukocytes, which are seen during migration ofleukocytes into the sites of inflammation, wherein IL-1, TNF-α and IL-8activate neutrophiles to cause release of lysosomal enzymes andproduction of active oxygen and prostaglandin, thus inducinginflammation. When IL-1, TNF-α and IL-6 migrate into the circulatorysystem, they act on liver to induce production of acute phaseinflammatory protein (e.g., CRP and SAA), and act on bone marrow toincrease neutrophiles and platelets. In inflammations of connectivetissues, such as rheumatoid arthritis (RA), IL-1 and TNF-α are said toactivate fibroblasts and osteoclastic cells and induce production ofprostaglandin and collagenase [Mebio, 11 (2), 18-23, (1994)].

As stated in the foregoing, IL-1 and TNF-α play a central role invarious aspects of inflammatory responses.

Meanwhile, IL-8 is produced not only by peripheral blood monocytes andtissue macrophages, but also be large granular lymphocytes (LGL) knownas natural killer cells, T lymphocytes and various tissues and cellssuch as fibroblasts, vascular endothelial cells and epidermalkeratinocytes. Examples of production stimulators include mitogenlectins such as LPS, PHA, PSK (Coriolus versicolor-derived protein-boundpolysaccharide, Krestin) and cytokines such as IL-1 and TNF-α.

Although most of these cells barely produce IL-8 constantly, uponstimulation with the above-mentioned IL-8 production stimulators, theyproduce more than 100 times greater amounts of IL-8 within 24 hours ascompared to the production without stimulation. For example, when humanperipheral blood monocytes are stimulated with PSK, IL-8 mRNA is inducedwithin an hour, and production amount of IL-8 mRNA reaches its peak in 3hours, and gradually decreases with time. Along with the induction ofIL-8 mRNA, IL-8 protein having neutrophile chemotaxisis ability isdetected in the medium at 3 hours after the stimulation and increaseswith time. IL-8 mRNA is induced in the same manner in time as in thestimulation of IL-1 and TNF-α. IL-8 is noticeably stable to proteaseproduced by activated macrophage and the like.

The in vitro biological activities of IL-8 include chemotacticpromotion, induction of degranulation, respiratory burst induction,lysosomal enzyme release induction, induction of adhesion tounstimulated or stimulated vascular endothelial cells, promotion ofextravascular migration, reinforcement of expression of adhesionfactors, leukotriene B₄-HETH release induction and the like with regardto neutrophiles; chemotactic promotion with regard to T cells;suppressive effect on IgE production by IL-4 with regard to B cells; andchemotactic promotion and histamine•leukotriene release induction withregard to basophils. IL-8 also has in vivo activities of induction ofmigration of neutrophiles and lymphocytes, induction of neutrophilia,reinforcement of vascular permeability, and neutrophile-dependentarthrosynovial destruction [Rinsho Men-eki, 25 (8), 1013-1020 (1993)].

As mentioned earlier, IL-8 has various effects on neutrophiles. It hasbeen gradually clarified that IL-8 also acts on T lymphocytes,basophils, monocytes, keratinocytes and melanoma cells, besidesneutrophiles. The biological activities and target cells thereof arefound to be diverse like other cytokines.

It has been known that IL-8 realizes, in vivo, migration of neutrophilesand lymphocytes at the sites of subcutaneous injections, and increaseshoming of T lymphocytes to local lymph nodes. It has been also knownthat an intravenous or intraperitoneal injection of IL-8 markedlyincreases neutrophile counts in peripheral blood, and administration inlarge amounts thereof causes destruction of alveoli. In addition, aninjection of IL-8 into rabbit intra-articular joint space is known tolead to arthrosynovial destruction with migration of large amounts ofneutrophiles. These results suggest strong inflammation induction byIL-8 in vivo.

In view of the fact that IL-8 has various actions besides chemotacticstimulation of neutrophile, that IL-8 was detected in synovial fluid inpatients with gout or rheumatic arthritis, that IL-8 was detected fromskin pieces of patients with dermatitis such as psoriasis, that IL-8like chemotactic factor is produced by peripheral blood monocytes inasthma, and that IL-8 was detected in peripheral blood of patients withsepsis which is considered to be one of the causes of adult respiratorydistress syndrome (ARDS), it is evident that IL-8 is involved in variousdiseases such as inflammation.

Therefore, a substance capable of suppressing cytokines responsible forinflammations, such as IL-1, IL-6, IL-8 and TNF-α, is extremely usefulas a new type of medicine for noninfectious or infectious diseasesaccompanied by neutrophile migration, which are represented by rheumaticdiseases (e.g., rheumatoid arthritis); arthritis due to gout; systemiclupus erythematosus; dermatopathy (e.g., psoriasis, pustulosis andatopic dermatitis); respiratory diseases (e.g., bronchial asthma,bronchitis, ARDS and diffused interstitial pneumonia); inflammatorybowel diseases (e.g., ulcerative colitis and Crohn's disease); acute orchronic hepatitis inclusive of fulminant hepatitis; acute or chronicglomerulonephritis; nephropyelitis; uveitis caused by Behoet disease andvogt-Koyanagi Harada disease; Mediterranean fever (polyserositis);ischemic diseases (e.g., myocardial infarction); and systemiccirculatory failure and multi-organ failure caused by sepsis. Inparticular, such substance is expected to be effective as ananti-inflammatory agent based on new action mechanisms.

With such background of the art, compounds having inhibitory activity oninflammatory cytokines, such as IL-8, have been recently reported. Forexample, Japanese Patent Application under PCT laid-open under Kohyo No.7-503017 discloses an imidazole derivative such as4-(4-fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl) imidazol as acytokine inhibitor; Japanese Patent Application under PCT laid-openunder Kohyo No. 7-503018 discloses pyridyl-substituted imidazolederivatives such as 1-(4-pyridyl)-2-(4-fluorophenyl)-4-phenylimidazol ascytokine inhibitors; and Japanese Patent Unexamined Publication No.3-34959 discloses naphthalenemethaneamino derivatives having cytokineinhibitory activity. However, these publications do not suggest thecompound of the present invention.

In addition, compounds having inhibitory activity on protease involvedin inflammatory diseases have been reported. For example, JapanesePatent Unexamined Publication No. 4-330094 disclosest-butyl-oxycarbonyl-trimethylsilyl-Ala-Pro-NH-CH[(CH₂)₃N₃]-B-pinandioleas a serine protease inhibitor of thrombin which inducespre-inflammatory changes of IL-1 and the like. Japanese Patent ExaminedPublication No. 7-53705 discloses phenylalanine derivatives such asN-(trans-4-amino-methylcyclohexylcarbonyl)-L-phenylalanine4-acetylanilide. However, this publication relates to a compoundcharacteristically having amino at one end of phenylalanine and4-aminomethyl-6-membered ring-carbonyl group at the other end, whichrelates to a protease inhibitor, and does not relate to an inflammatorycytokine production suppressor, such as the compound of the presentinvention.

An object of the present invention is to provide a compound usable as anovel selective anti-inflammatory agent which suppresses production andrelease of inflammatory cytokines such as IL-8, IL-1, TNF-α, IL-6, andthe like.

In addition, an object of the present invention is to provide apharmaceutical agent comprising said compound.

DISCLOSURE OF THE INVENTION

The present inventors have conducted intensive studies with the aim ofachieving the above-mentioned objects and completed the presentinvention.

Accordingly, the present invention provides the following.

(1) An amide compound of the formula (I):

 

wherein:

-   R is an optionally substituted non-aromatic heterocyclic group    containing nitrogen, a hydroxy, R_(a), an alkoxy substituted by    R_(a), an alkylthio substituted by R_(a), or an alkylamino    substituted by R_(a),    -   wherein R_(a) is amino, guanidino, amidino, carbamoyl, ureido,        thioureido, hydrazino, hydrazinocarbonyl or imino, these groups        being optionally substituted by a substituent selected from the        group consisting of lower alkyl, halogenated lower alkyl,        cycloalkyl, aralkyl, aryl and amino-protecting group;-   A is an optionally substituted, linear or branched alkylene which    optionally has one or more double bond(s) or triple bond(s) in the    chain, or a single bond;-   X is an oxygen atom, a sulfur atom, a cycloalkylene, a divalent    aromatic heterocyclic group having one or more hetero atom(s)    selected from the group consisting of a nitrogen atom, sulfur atom    and oxygen atom, —SO—, —SO₂—, —C═C—, —C≡C—, —CO—, —COO—, —OOC—,    —CS—, —COS—, —O—CO—O—, —NH—CO—NH—, —NH—CS—NH—, —NH—C (═NH)—NH—,    —NR⁸—, —NR⁸CO—, —CONR⁸—, —NR⁸SO₂—, —SO₂NR⁸—, —NR⁸—NR⁸—, or —CR⁹R¹⁰—    -   wherein R⁸ is hydrogen atom, alkyl, cycloalkyl, aryl, aralkyl or        amino-protecting group, and R⁹ and R¹⁰ are the same or different        and each is hydrogen atom, alkyl, cycloalkyl, aryl or aralkyl;-   M is an arylene, a cycloalkylene, or a divalent heterocyclic group    which has one or more hetero atom(s) selected from the group    consisting of a nitrogen atom, sulfur atom and oxygen atom, and    which optionally forms a fused ring;-   R¹, R², R³ and R⁴ are the same or different and each is a hydrogen    atom, a hydroxy, a halogen atom, an alkoxy, a mercapto, an    alkylthio, a nitro, a cyano, a carboxy, an alkoxycarbonyl, an    aryloxycarbonyl, an acyl, an alkyl optionally substituted by a    substituent selected from the group consisting of hydroxy, lower    alkoxy and halogen atom, an amino optionally substituted by a    substituent selected from the group consisting of alkyl, aryl,    aralkyl and amino-protecting group, or —O—CO—R¹¹    -   wherein R¹¹ is optionally substituted alkoxy, optionally        substituted aryl, optionally substituted cycloalkyl, optionally        substituted aryloxy, optionally substituted aralkyloxy,        optionally substituted alkylthio, optionally substituted        arylthio, or alkyl optionally substituted by a substituent        selected from the group consisting of alkoxycarbonyl, acyloxy,        aryl, aryloxy, aryloxycarbonyl, aralkyloxy, aralkyloxycarbonyl,        alkylthio, arylthio, acyl, lower alkoxy, carboxy, halogen atom        and amino optionally substituted by lower alkyl or acyl;-   R⁵ is a hydrogen atom, an alkyl optionally substituted by halogen    atom, an optionally substituted aralkyl, or an amino-protecting    group;-   m is 0 or an integer of 1-6;-   R⁶ is an optionally substituted aryl, an optionally substituted    cycloalkyl, an optionally substituted lower alkyl, an optionally    substituted lower alkoxy, an optionally substituted lower alkylthio,    an amino optionally substituted by a substituent selected from the    group consisting of lower alkyl, aryl, aralkyl and amino-protecting    group, or an optionally substituted heterocyclic group having one    ore more hetero atoms selected from the group consisting of a    nitrogen atom, sulfur atom and oxygen atom; and-   R⁷ is a hydrogen atom, an optionally substituted alkyl, an    optionally substituted aryl, an optionally substituted aromatic    heterocyclic group having one ore more hetero atoms selected from    the group consisting of a nitrogen atom, sulfur atom and oxygen    atom, or —CO(Y)_(p)R¹²    -   wherein Y is oxygen atom, sulfur atom, —NR¹³— or —NR¹³—SO₂—        -   wherein R¹³ is hydrogen atom, alkyl, aralkyl, hydroxy,            alkoxy, aryl or amino-protecting group,        -   p is 0 or 1, and R¹² is hydrogen atom, optionally            substituted alkenyl, optionally substituted alkynyl,            optionally substituted cycloalkyl, optionally substituted            aryl, optionally substituted aralkyl, adamantyl,            cycloalkylideneamino, optionally substituted heterocyclic            group having one or more hetero atom(s) selected from the            group consisting of nitrogen atom, sulfur atom and oxygen            atom, or alkyl optionally substituted by a substituent            selected from the group consisting of hydroxy, alkoxy,            alkoxyalkoxy, alkoxycarbonyl, acyloxy, carboxy, heterocyclic            group having one or more hetero atom(s) selected from the            group consisting of nitrogen atom, sulfur atom and oxygen            atom, and amino optionally substituted by a substituent            selected from the group consisting of alkyl, aryl, aralkyl            and amino-protecting group;-   and a pharmaceutically acceptable acid addition salt thereof.    (2) The amide compound of (1) above, wherein, in the formula (I), at    least one symbol selected from the group consisting of R, A, X, R¹,    R², R³, R⁴, R⁵, m, R⁶ and R⁷ satisfies the following definitions,    and a pharmaceutically acceptable acid addition salt thereof:-   R is a non-aromatic heterocyclic group containing nitrogen, which is    optionally substituted by lower alkyl or amino-protecting group,    R_(a1), an alkoxy substituted by R_(a1), an alkylthio substituted by    R_(a1), or an alkylamino substituted by R_(a1),    -   wherein R_(a1) is amino, guanidino, amidino, carbamoyl, ureido,        thioureido, hydrazino, hydrazinocarbonyl or imino, these groups        being optionally substituted by a substituent selected from the        group consisting of lower alkyl, aralkyl and amino-protecting        group;-   A is a linear or branched alkylene which optionally has one or more    double bond(s) or triple bond(s) in the chain, or a single bond;-   X is an oxygen atom, a sulfur atom, a cycloalkylene, a divalent    aromatic heterocyclic group having one or more hetero atom(s)    selected from the group consisting of a nitrogen atom, sulfur atom    and oxygen atom, —SO—, —SO₂—, —C═C—, —C≡C—, —CO—, —COO—, —OOC—,    —CS—, —COS—, —O—CO—O—, —NH—CO—NH—, —NH—CS—NH—, —NH—C (═NH)—NH—,    —NR⁸′—, —NR⁸′CO—, —CONR⁸′—, —NR⁸′SO₂—, —SO₂NR⁸′—, —NR⁸′—COO—,    —OOC—NR⁸′—, or —CR⁹′R¹⁰′—    -   wherein R⁸′ is hydrogen atom, lower alkyl, aralkyl or        amino-protecting group, and R⁹′ and R¹⁰′ are the same or        different and each is hydrogen atom, lower alkyl or aralkyl;-   M is an arylene, a cycloalkylene, or a divalent heterocyclic group    which has one or more hetero atom(s) selected from the group    consisting of a nitrogen atom, sulfur atom and oxygen atom, and    which optionally forms a fused ring;-   R¹, R², R³ and R⁴ are the same or different and each is a hydrogen    atom, a hydroxy, a halogen atom, an lower alkoxy, a mercapto, a    lower alkylthio, a nitro, a cyano, a carboxy, a lower    alkoxycarbonyl, an aryloxycarbonyl, an acyl, a lower alkyl    optionally substituted by a substituent selected from the group    consisting of hydroxy, lower alkoxy and halogen atom, an amino    optionally substituted by a substituent selected from the group    consisting of lower alkyl, aralkyl and amino-protecting group, or    —O—CO—R¹¹′    -   wherein R¹¹′ is lower alkoxy, optionally substituted cycloalkyl,        lower alkyl optionally substituted by a substituent selected        from the group consisting of lower alkoxy-carbonyl, acyloxy,        aralkyloxy, aralkyloxycarbonyl, acyl, lower alkoxy, carboxy and        amino optionally substituted by lower alkyl, or aryl optionally        substituted by a substituent selected from the group consisting        of lower alkyl, carboxy and benzyloxycarbonyl;-   R⁵ is a hydrogen atom, an alkyl optionally substituted by halogen    atom, an optionally substituted aralkyl, or an amino-protecting    group;-   m is 0 or an integer of 1-6;-   R⁶ is aryl, a cycloalkyl, or a heterocyclic group having one or more    hetero atom(s) selected from the group consisting of a nitrogen    atom, sulfur atom and oxygen atom    -   where said aryl, cycloalkyl and heterocyclic group having one or        more hetero atom(s) selected from the group consisting of        nitrogen atom, sulfur atom and oxygen atom are optionally        substituted by a substituent selected from the group consisting        of lower alkyl, halogen atom, hydroxy, lower alkoxy, amino,        carboxy and lower alkoxycarbonyl; and-   R⁷ is a hydrogen atom, a lower alkyl optionally substituted by a    substituent selected from the group consisting of hydroxy, lower    alkoxy, mercapto, lower alkylthio, carboxy, lower alkoxycarbonyl and    amino, an aromatic heterocyclic group which has one or more hetero    atom(s) selected from the group consisting of a nitrogen atom,    sulfur atom and oxygen atom, and which is optionally substituted by    lower alkyl, or —CO(Y′)_(p)R¹²′    -   wherein Y′ is oxygen atom, sulfur atom, —NR¹³′— or —NR¹³′—SO₂—        -   wherein        -   R¹³′ is hydrogen atom, lower alkyl, aralkyl, hydroxy, lower            alkoxy or amino-protecting group,        -   p is 0 or 1, and R¹²′ is hydrogen atom, aralkyl, adamantyl,            cycloalkylideneamino, cycloalkyl optionally substituted by a            lower alkyl, alkyl optionally substituted by a substituent            selected from the group consisting of hydroxy, lower alkoxy,            lower alkoxy lower alkoxy, lower alkoxycarbonyl, acyloxy,            carboxy, heterocyclic group having one or more hetero            atom(s) selected from the group consisting of, nitrogen            atom, sulfur atom and oxygen atom, and amino optionally            substituted by a substituent selected from the group            consisting of lower alkyl, aralkyl and amino-protecting            group, aryl optionally substituted by a substituent selected            from the group consisting of lower alkyl, halogen atom,            amino, carboxy, hydroxy and lower alkoxy, or heterocyclic            group which is optionally substituted by a substituent            selected from the group consisting of lower alkyl, halogen            atom, amino, carboxy, hydroxy and lower alkoxy, and which            has one or more hetero atom(s) selected from the group            consisting of nitrogen atom, sulfur atom and oxygen atom.            (3) The amide compound of (1) above, wherein, in the formula            (I), at least one symbol selected from the group consisting            of R, A, X, R¹, R², R³, R⁴, R⁵, m, R⁶ and R⁷ satisfies the            following definitions, and a pharmaceutically acceptable            acid addition salt thereof:-   R is a non-aromatic heterocyclic group containing nitrogen, which is    optionally substituted by lower alkyl or amino-protecting group,    R_(a2), or an alkoxy substituted by R_(a2),    -   wherein R_(a2) is amino, guanidino, amidino or carbamoyl, these        groups being optionally substituted by a lower alkyl or        amino-protecting group;-   A is a linear alkylene or a single bond;-   X is an oxygen atom, a sulfur atom, a divalent aromatic heterocyclic    group having one or more hetero atom(s) selected from the group    consisting of a nitrogen atom, sulfur atom and oxygen atom, —COO—,    —OOC—, NR⁸″—, —NR⁸″—CO—, —CONR⁸″—, —NR⁸″SO₂—, —SO₂NR⁸″—, or    —CR⁹″R¹⁰″    -   wherein R⁸″ is hydrogen atom, lower alkyl or amino-protecting        group, and R⁹″ and R¹⁰″ are the same or different and each is        hydrogen atom or lower alkyl;-   M is an arylene or a divalent heterocyclic group which has one or    more hetero atom(s) selected from the group consisting of a nitrogen    atom, sulfur atom and oxygen atom, and which optionally forms a    fused ring;-   R¹, R², R³ and R⁴ are the same or different and each is a hydrogen    atom, a hydroxy, a halogen atom, lower alkoxy, a lower alkyl    optionally substituted by a substituent selected from the group    consisting of hydroxy, lower alkoxy and halogen atom, or —O—CO—R¹¹″    -   wherein R¹¹′ is lower alkoxy, cycloalkyl, aryl optionally        substituted by lower alkyl, or lower alkyl optionally        substituted by a substituent selected from the group consisting        of acyloxy, aralkyloxycarbonyl and amino optionally substituted        by lower alkyl;-   R⁵ is a hydrogen atom, a lower alkyl, or an amino-protecting group;-   m is 1;-   R⁶ is an aryl or a cycloalkyl    -   wherein said aryl and cycloalkyl are optionally substituted by        halogen atom or hydroxy; and-   R⁷ is a hydrogen atom, a lower alkyl optionally substituted by    hydroxy or lower alkoxy, an aromatic heterocyclic group having one    ore more hetero atom(s) selected from the group consisting of a    nitrogen atom, sulfur atom and oxygen atom, and which is optionally    substituted by lower alkyl, or —CO(Y″)_(p)R¹²″    -   wherein Y″ is oxygen atom, sulfur atom or —NR¹³″—        -   wherein        -   R¹³″ is hydrogen atom, lower alkyl, hydroxy, or            amino-protecting group,        -   p is 0 or 1, and R¹²″ is hydrogen atom, aralkyl, adamantyl,            cycloalkylideneamino, cycloalkyl optionally substituted by            lower alkyl, aryl optionally substituted by halogen atom,            alkyl optionally substituted by a substituent selected from            the group consisting of hydroxy, lower alkoxy, lower alkoxy            lower alkoxy, lower alkoxycarbonyl, acyloxy, carboxy,            heterocyclic group having one or more hetero atom(s)            selected from the group consisting of nitrogen atom, sulfur            atom and oxygen atom, and amino optionally substituted by a            substituent selected from the group consisting of lower            alkyl, aralkyl and amino-protecting group, or heterocyclic            group which is optionally substituted by lower alkyl, and            which has one or more hetero atom(s) selected from the group            consisting of nitrogen atom, sulfur atom and oxygen atom.            (4) The amide compound of (1) above, wherein, in the formula            (I), at least one symbol selected from the group consisting            of R, A, X, R¹, R², R³, R⁴, R⁵, m, R⁶ and R⁷ satisfies the            following definitions, and a pharmaceutically acceptable            acid addition salt thereof:-   R is a piperazinyl optionally substituted by lower alkyl, a    piperidyl optionally substituted by lower alkyl, an amino, or a    lower alkoxy substituted by amino    -   wherein amino is optionally substituted by lower alkyl;-   A is a linear alkylene;-   X is an oxygen atom, a sulfur atom, —NH— or —CH₂—;-   M is an arylene;-   R¹, R², R³ and R⁴ are the same or different and each is a hydrogen    atom, a hydroxy, a halogen atom, or —O—CO—R¹¹″′    -   wherein R¹¹″′ is lower alkyl optionally substituted by a        substituent selected from the group consisting of amino, acyloxy        and benzyloxycarbonyl, or phenyl optionally substituted by lower        alkyl;-   R⁵ is a hydrogen atom;-   m is 1;-   R⁶ is a phenyl; and-   R⁷ is —COO—R¹²″′    -   wherein R¹²″′ is hydrogen atom, aralkyl, adamantyl,        cyclohexylideneamino, cyclohexyl optionally substituted by lower        alkyl, piperidyl optionally substituted by lower alkyl, or alkyl        optionally substituted by a substituent selected from the group        consisting of hydroxy, lower alkoxy, lower alkoxy lower alkoxy,        lower alkoxycarbonyl, acyloxy, piperazinyl and amino optionally        substituted by lower alkyl.        (5) The amide compound of (4) above, wherein M is phenylene, and        a pharmaceutically acceptable acid addition salt thereof.        (6) The amide compound of (4) above, wherein R⁷ is —COO—R^(12″″)        wherein R^(12″″) is lower alkyl, or cyclohexyl which is        optionally substituted by lower alkyl, and a pharmaceutically        acceptable acid addition salt thereof.        (7) The amide compound of (4) above, wherein X is oxygen atom or        —CH₂—, and a pharmaceutically acceptable acid addition salt        thereof.        (8) The amide compound of (4) above, wherein R⁶ is phenyl and m        is 1, and a pharmaceutically acceptable acid addition salt        thereof.        (9) The amide compound of (4) above, wherein R is amino        optionally substituted by lower alkyl, piperazinyl optionally        substituted by lower alkyl, or piperidyl optionally substituted        by lower alkyl, and a pharmaceutically acceptable salt addition        salt thereof.        (10) The amide compound of (4) above, wherein R¹, R², R³ and R⁴        are the same or different and each is hydrogen atom, hydroxy,        halogen atom, or —O—CO—R¹¹″″ wherein R¹¹″″ is lower alkyl or        phenyl, and a pharmaceutically acceptable acid addition salt        thereof.        (11) An carboxylic acid compound of the formula (I-a):                 wherein:-   R is an optionally substituted non-aromatic heterocyclic group    containing nitrogen, a hydroxy, R_(a), an alkoxy substituted by    R_(a), an alkylthio substituted by R_(a), or an alkylamino    substituted by R_(a),    -   wherein R_(a) is amino, guanidino, amidino, carbamoyl, ureido,        thioureido, hydrazino, hydrazinocarbonyl or imino, these groups        being optionally substituted by a substituent selected from the        group consisting of lower alkyl, halogenated lower alkyl,        cycloalkyl, aralkyl, aryl and amino-protecting group;-   A is an optionally substituted, linear or branched alkylene which    optionally has one or more double bond(s) or triple bond(s) in the    chain, or a single bond;-   X is an oxygen atom, a sulfur atom, a cycloalkylene, a divalent    aromatic heterocyclic group having one ore more hetero atoms    selected from the group consisting of a nitrogen atom, sulfur atom    and oxygen atom, —SO—, —SO₂—, —C═C—, —C≡C—, —CO—, —COO—, —OOC—,    —CS—, —COS—, —O—CO—O—, —NH—CO—NH—, —NH—CS—NH—, —NH—C (═NH)—NH—,    —NR⁸—, —NR⁸CO—, —CONR⁸—, —NR⁸SO₂—, —SO₂NR⁸—, —NR⁸—COO—, —OOC—NR⁸—,    or —CR⁹R¹⁰—    -   wherein R⁸ is hydrogen atom, alkyl, cycloalkyl, aryl, aralkyl or        amino-protecting group, and R⁹ and R¹⁰ are the same or different        and each is hydrogen atom, alkyl, cycloalkyl, aryl or aralkyl;-   M is an arylene, a cycloalkylene, or a divalent heterocyclic group    which has one ore more hetero atoms selected from the group    consisting of a nitrogen atom, sulfur atom and oxygen atom, and    which optionally forms a fused ring; and-   R¹, R², R³ and R⁴ are the same or different and each is a hydrogen    atom, a hydroxy, a halogen atom, an alkoxy, a mercapto, an    alkylthio, a nitro, a cyano, a carboxy, an alkoxycarbonyl, an    aryloxycarbonyl, an acyl, an alkyl optionally substituted by a    substituent selected from the group consisting of hydroxy, lower    alkoxy and halogen atom, an amino optionally substituted by a    substituent selected from the group consisting of alkyl, aryl,    aralkyl and amino-protecting group, or —O—CO—R¹¹    -   wherein R¹¹ is optionally substituted alkoxy, optionally        substituted aryl, optionally substituted cycloalkyl, optionally        substituted aryloxy, optionally substituted aralkyloxy,        optionally substituted alkylthio, optionally substituted        arylthio, or alkyl optionally substituted by a substituent        selected from the group consisting of alkoxycarbonyl, acyloxy,        aryl, aryloxy, aryloxycarbonyl, aralkyloxy, aralkyloxycarbonyl,        alkylthio, arylthio, acyl, lower alkoxy, carboxy, halogen atom        and amino optionally substituted by lower alkyl or acyl;        (12) The carboxylic acid compound of (1) above, wherein, in the        formula (I-a), at least one of R, A, X, M, R¹, R², R³ and R⁴        satisfies the following definitions:-   R is a piperazinyl optionally substituted by lower alkyl, a    piperidyl optionally substituted by lower alkyl, an amino or a lower    alkoxy substituted by amino    -   wherein amino is optionally substituted by lower alkyl;-   A is a linear alkylene;-   X is an oxygen atom, a sulfur atom, —NH— or —CH₂—;    -   M is an arylene; and-   R¹, R², R³ and R⁴ are the same or different and each is a hydrogen    atom, a hydroxy, a halogen atom, or —O—CO—R¹¹″′    -   wherein R¹¹′″ is lower alkyl optionally substituted by a        substituent selected from the group consisting of amino, acyloxy        and benzyloxycarbonyl, or phenyl optionally substituted by lower        alkyl.        (13) An amide compound of the formula (I-b)         -   X is an oxygen atom, a sulfur atom, a cycloalkylene, a divalent    aromatic heterocyclic group having one ore more hetero atom(s)    selected from the group consisting of a nitrogen atom, sulfur atom    and oxygen atom, —SO—, —SO₂—, —C═C—, —C≡C—, —CO—, —COO—, —OOC—,    —CS—, —COS—, —O—CO—O—, —NH—CO—NH—, —NH—CS—NH—, —NH—C (═NH)—NH—,    —NR⁸—, —NR⁸CO—, —CONR⁸—, —NR⁸SO₂—, —SO₂NR⁸—, —NR⁸—COO—, —OOC—NR⁸— or    —CR⁹R¹⁰—    -   wherein R⁸ is hydrogen atom, alkyl, cycloalkyl, aryl, aralkyl or        amino-protecting group, and R⁹ and R¹⁰ are the same or different        and each is hydrogen atom, alkyl, cycloalkyl, aryl or aralkyl;-   M is an arylene, a cycloalkylene, or a divalent heterocyclic group    which has one ore more hetero atom(s) selected from the group    consisting of a nitrogen atom, sulfur atom and oxygen atom, and    which optionally forms a fused ring;-   R¹, R², R³ and R⁴ are the same or different and each is a hydrogen    atom, a hydroxy, a halogen atom, an alkoxy, a mercapto, an    alkylthio, a nitro, a cyano, a carboxy, an alkoxycarbonyl, an    aryloxycarbonyl, an acyl, an alkyl optionally substituted by a    substituent selected from the group consisting of hydroxy, lower    alkoxy and halogen atom, an amino optionally substituted by a    substituent selected from the group consisting of alkyl, aryl,    aralkyl and amino-protecting group, or —O—R¹¹    -   wherein R¹¹ is optionally substituted alkoxy, optionally        substituted aryl, optionally substituted cycloalkyl, optionally        substituted aryloxy, optionally substituted aralkyloxy,        optionally substituted alkylthio, optionally substituted        arylthio, or alkyl optionally substituted by a substituent        selected from the group consisting of alkoxycarbonyl, acyloxy,        aryl, aryloxy, aryloxycarbonyl, aralkyloxy, aralkyloxycarbonyl,        alkylthio, arylthio, acyl, lower alkoxy, carboxy, halogen atom        and amino optionally substituted by lower alkyl or acyl;-   R⁵ is a hydrogen atom, an alkyl optionally substituted by halogen    atom, optionally substituted aralkyl, or an amino-protecting group;-   m is 0 or an integer of 1-6;-   R⁶ is an optionally substituted aryl, an optionally substituted    cycloalkyl, an optionally substituted lower alkyl, an optionally    substituted lower alkoxy, an optionally substituted lower alkylthio,    an amino optionally substituted by a substituent selected from the    group consisting of lower alkyl, aryl, aralkyl and amino-protecting    group, or an optionally substituted heterocyclic group having one or    more hetero atom(s) selected from the group consisting of a nitrogen    atom, sulfur atom and oxygen atom; and-   R⁷ is a hydrogen atom, an optionally substituted alkyl, an    optionally substituted aryl, an optionally substituted aromatic    heterocyclic group having one or more hetero atom(s) selected from    the group consisting of a nitrogen atom, sulfur atom and oxygen    atom, or —CO(Y)_(p)R¹²    -   wherein Y is oxygen atom, sulfur atom, —NR¹³— or —NR¹³—SO₂—        -   wherein        -   R¹³ is hydrogen atom, alkyl, aralkyl, hydroxy, alkoxy, aryl            or amino-protecting group,        -   p is 0 or 1, and R¹² is hydrogen atom, optionally            substituted alkenyl, optionally substituted alkynyl,            optionally substituted cycloalkyl, optionally substituted            aryl, optionally substituted aralkyl, adamantyl,            cycloalkylideneamino, alkyl optionally substituted by a            substituent selected from the group consisting of hydroxy,            alkoxy, alkoxyalkoxy, alkoxycarbonyl, acyloxy, carboxy,            heterocyclic group having one or more hetero atom(s)            selected from the group consisting of a nitrogen atom,            sulfur atom and oxygen atom, and amino optionally            substituted by a substituent selected from the group            consisting of alkyl, aryl, aralkyl and amino-protecting            group, or optionally substituted heterocyclic group having            one or more hetero atom(s) selected from the group            consisting of a nitrogen atom, sulfur atom and oxygen atom.            (14) The amide compound of (13) above, wherein, in the            formula (I-b), at least one symbol selected from the group            consisting of X, M, R¹, R², R³, R⁴, R⁵, m, R⁶ and R⁷            satisfies the following definitions:-   X is an oxygen atom, a sulfur atom or —NH—;-   M is an arylene;-   R¹, R², R³ and R⁴ are the same or different and each is a hydrogen    atom, a hydroxy, a halogen atom, or —O—CO—R¹¹″′    -   wherein R¹¹″′ is lower alkyl optionally substituted by a        substituent selected from the group consisting of amino, acyloxy        and benzyloxycarbonyl, or a phenyl optionally substituted by        lower alkyl;-   R⁵ is a hydrogen atom;-   m is 1;-   R⁶ is a phenyl; and-   R⁷ is —COO—R¹²″′    -   wherein R¹²″′ is hydrogen atom, aralkyl, adamantyl,        cyclohexyl-ideneamino, piperidyl optionally substituted by lower        alkyl, cyclohexyl optionally substituted by lower alkyl, or        alkyl optionally substituted by a substituent selected from the        group consisting of hydroxy, lower alkoxy, lower alkoxy lower        alkoxy, lower alkoxycarbonyl, acyloxy, piperazinyl, and amino        optionally substituted by lower alkyl.        (15) A pharmaceutical composition comprising a pharmaceutically        acceptable carrier, and the amide compound of any one of (1)        to (10) above or a pharmaceutically acceptable acid addition        salt thereof.        (16) An inflammatory cytokine production suppressor comprising        the amide compound of any one of (1) to (10) above or a        pharmaceutically acceptable acid addition salt thereof as an        active ingredient.        (17) An agent for the treatment or prophylaxis of an        inflammatory diseases, comprising the amide compound of any one        of (1) to (10) above or a pharmaceutically acceptable acid        addition salt thereof as an active ingredient.

In the present specification, each substituent means as follows.

“Alkoxy” is linear or branched alkoxy having 1 to 6 carbon atoms, whichis exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy,neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy and neohexyloxy,with preference given to linear or branched alkoxy having 1 to 4 carbonatoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy and tert-butoxy.

“Lower alkoxy” is linear or branched alkoxy having 1 to 4 carbon atoms,which is exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy and tert-butoxy, with preference given to methoxyand ethoxy.

“Alkylthio” is linear or branched alkylthio having 1 to 6 carbon atoms,which is exemplified by methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio,pentylthio, isopentylthio, neopentylthio, tert-pentylthio, hexylthio,isohexylthio and neohexylthio.

“Lower alkylthio” is linear or branched alkylthio having 1 to 4 carbonatoms, which is exemplified by methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, sec-butylthio andtert-butylthio.

“Alkylamino” is linear or branched, monoalkylamino or dialkylamino whichhas 1 to 6 carbon atoms, which is exemplified by methylamino,dimethylamino, ethylamino, diethylamino, methylethylamino, propylamino,isopropylamino, butylamino, isobutylamino, sec-butylamino,tert-butylamino, pentylamino, isopentylamino, neopentylamino,tert-pentylamino, hexylamino, isohexylamino and neohexylamino, withpreference given to linear alkylamino, such as methylamino,dimethylamino, ethylamino, diethylamino, propylamino, butylamino,pentylamino and hexylamino. Particularly preferred is linear alkylaminohaving 1 to 4 carbon atoms, which is exemplified by methylamino,dimethylamino, ethylamino, diethylamino, propylamino and butylamino.

“Non-aromatic heterocyclic group containing nitrogen” is 3- to7-membered non-aromatic heterocyclic group which has at least onenitrogen atom and optionally a sulfur atom or oxygen atom, and which isoptionally fused with benzene ring. Specific examples thereof includeaziridinyl, thiazetidinyl, azetidinyl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, morpholinyl,morpholino, oxazinyl, thiazinyl, piperazinyl, piperidyl, piperidino,dioxazepinyl, thiazepinyl, diazepinyl, perhydrodiazepinyl, azepinyl,perhydroazepinyl, indolinyl and isoindolinyl. Preferred are aziridinyl,azetidinyl, pyrrolidinyl, pyrazolidinyl, morpholinyl, morpholino,piperazinyl, piperidyl, piperidino and perhydroazepinyl, andparticularly preferred are pyrrolidinyl, morpholino, piperazinyl,piperidyl and piperidino.

“Alkyl” is linear or branched alkyl having 1 to 6 carbon atoms, which isexemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl,isohexyl and neo-hexyl.

“Lower alkyl” is linear or branched alkyl having 1 to 4 carbon atoms,which is exemplified by methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl and tert-butyl.

“Halogen atom” is specifically a fluorine atom, chlorine atom, bromineatom or iodine atom.

“Halogenated lower alkyl” is that wherein the abovementioned lower alkylis substituted by a halogen atom, and is exemplified by fluoromethyl,chloromethyl, bromomethyl, difluoromethyl, dichloromethyl,trifluoromethyl, trichloromethyl, difluoroethyl, dichloroethyl,pentatrifluoroethyl, trichloroethyl and fluoropropyl, with preferencegiven to fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl andtrifluoromethyl.

“Cycloalkyl” is that having 3 to 7 carbon atoms, which is exemplified bycyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, withpreference given to cycloalkyl having 5 or 6 carbon atoms, such ascyclopentyl and cyclohexyl.

“Aralkyl” is that wherein alkyl is substituted by aryl and isexemplified by benzyl, benzhydryl, trityl, phenethyl, 3-phenylpropyl,2-phenylpropyl, 4-phenylbutyl and naphthylmethyl, with preference givento benzyl and phenethyl.

“Aralkyloxy” is that having the above-mentioned aralkyl, which isexemplified by benzyloxy, benzhydryloxy, tritryloxy, phenethyloxy,3-phenylpropyloxy, 2-phenylpropyloxy, 4-phenylbutyloxy andnaphthylmethoxy, with preference given to benzyloxy and phenethyloxy.

“Aralkyloxycarbonyl” is that having the above-mentioned aralkyl, whichis exemplified by benzyloxycarbonyl, benzhydryloxycarbonyl,trityloxycarbonyl, phenethyloxycarbonyl, 3-phenylpropyloxycarbonyl,2-phenylpropyloxycarbonyl, 4-phenylbutyloxycarbonyl andnaphthylmethoxy-carbonyl, with preference given to benzyloxycarbonyl andphenethyloxy-carbonyl.

“Aryl” is phenyl, naphthyl, anthryl, phenanthryl or biphenyl, withpreference given to phenyl and naphthyl. “Aryloxy” is that having theabove-mentioned aryl, which is exemplified by phenoxy and naphthyloxy.

“Aryloxycarbonyl” is that having the above-mentioned aryl, which isexemplified by phenoxycarbonyl and naphthyloxycarbonyl.

“Arylthio” is that having the above-mentioned aryl, which is exemplifiedby phenylthio and naphthylthio.

“Amino-protecting group” is a protecting group conventionally used,which is subject to no particular limitation as long as it protectsamino from various reactions. Specific examples include acyl such asformyl, acetyl, propionyl, butyryl, oxalyl, succinyl, pivaloyl,2-chloroacetyl, 2-bromoacetyl, 2-iodoacetyl, 2,2-dichloroacetyl,2,2,2-trichloroacetyl, 2,2,2-trifluoroacetyl, phenylacetyl,phenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl,4-nitrobenzoyl, naphthyl-carbonyl, adamantylcarbonyl and phthaloyl;alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, cyclohexyloxycarbonyl, 2-chloroethoxycarbonyl,2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-trichloro-tert-butoxycarbonyl, benzhydryloxycarbonyl,bis-(4-methoxyphenyl)methoxycarbonyl, phenacyloxy-carbonyl,2-trimethylsilylethoxycarbonyl, 2-triphenylsilylethoxycarbonyl andfluorenyl-9-methoxycarbonyl; alkenyloxycarbonyl such asvinyloxycarbonyl, 2-propenyloxycarbonyl, 2-chloro-2-propenyloxycarbonyl,3-methoxycarbonyl-2-propenyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl,2-butenyloxycarbonyl and cinnamyloxycarbonyl; aralkyloxycarbonyl such asbenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl and phenethyloxycarbonyl; loweralkylsilyl such as trimethyl-silyl and tert-butyldimethylsilyl;alkylenebis (dialkylsilyl) such as ethylenebis(dimethylsilyl),propylenebis(dimethylsilyl) and ethylene-bis(diethylsilyl);alkylthiocarbonyl such as methylthiocarbonyl, ethylthiocarbonyl,butylthiocarbonyl and tert-butylthiocarbonyl; aralkylthiocarbonyl suchas benzylthiocarbonyl; phosphoryl such as dicyclohexylphosphoryl,diphenylphosphoryl, dibenzylphosphoryl, di-(4-nitrobenzyl)phosphoryl andphenoxyphenylphosphoryl; and phosphinyl such as diethylphosphinyl,diphenylphosphinyl.

“Linear or branched alkylene optionally having one or more doublebond(s) or triple bond(s) in the chain” is linear or branched alkylenehaving 1 to 10 carbon atoms, which may have one ore more double bonds ortriple bonds in the chain, and is exemplified by methylene, ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, octamethylene, nonamethylene, decamethylene,dimethylmethylene, diethylmethylene, propylene, methylethylene,ethylethylene, propylethylene, isopropylethylene, methylpentaethylene,ethylhexamethylene, dimethylethylene, methyltriethylene,dimethyltrimethylene, vinylene, propenylene, butenylene, butadienylene,pentenylene, pentadienylene, hexenylene, hexadienylene, hexatrienylene,heptenylene, heptadienylene, heptatrienylene, octenylene, octadienylene,octatrienylene, octatetraenylene, propynylene, butynylene, pentynyleneand methylpropynylene, with preference given to linear alkylene, such asmethylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, heptamethylene, octamethylene, nonamethylene,decamethylene, vinylene, propenylene, butenylene, butadienylene,pentenylene, pentadienylene, hexenylene, hexadienylene, hexatrienylene,heptenylene, heptadienylene, heptatrienylene, octenylene, octadienylene,octatrienylene, octatetraenylene, propynylene, butynylene andpentynylene. Particularly preferred is linear alkylene having 1 to 8carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, heptamethylene and octamethylene.

“Divalent aromatic heterocyclic group having one or more hetero atom(s)selected from the group consisting of a nitrogen atom, sulfur atom andoxygen atom” is 5- or 6-membered divalent aromatic heterocyclic grouphaving one or more hetero atom(s) selected from the group consisting ofa nitrogen atom, sulfur atom and oxygen atom, which is exemplified bydivalent groups of tetrazole ring, oxadiazole ring, thiadiazole ring,triazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazolering, imidazole ring, pyrazole ring, pyrrole ring, furan ring, thiopenering, tetrazine ring, triazine ring, pyrazine ring, pyridazine ring,pyrimidine ring and pyridine ring. Preferred is 5-membered divalentaromatic heterocyclic group, which is exemplified by divalent groups oftetrazole ring, oxadiazole ring, thiadiazole ring, triazole ring,oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazolering, pyrazole ring, pyrrole ring, furan ring and thiophene ring.Particularly preferred are divalent groups of oxadiazole ring,thiadiazole ring and triazole ring.

“Cycloalkylene” is that having 3 to 7 carbon atoms, namely, divalentcycloalkyl, which is specifically exemplified by cyclopropylene,cyclobutylene, cyclopentylene, cyclohexylene and cycloheptylene.Preferred is cycloalkylene having 5 or 6 carbon atoms, which isexemplified by cyclopentylene and cyclohexylene.

“Arylene” is exemplified by phenylene, naphthylene, anthrylene,phenanthrylene and biphenylene, with preference given to phenylene,naphthylene and biphenylene.

“Divalent heterocyclic group which has one or more hetero atom(s)selected from the group consisting of a nitrogen atom, sulfur atom andoxygen atom, and which optionally forms a fused ring” is specificallyexemplified by divalent heterocyclic groups of dioxolane ring, dithiolring, pyrrolidine ring, morpholine ring, oxazine ring, piperazine ring,piperidine ring, pyrroline ring, imidazolidine ring, imidazoline ring,pyrazolidine ring, pyrazoline ring, thiatriazole ring, tetrazole ring,oxadiazole ring, thiadiazole ring, triazole ring, isoxazole ring,oxazole ring, thiazole ring, imidazole ring, pyrazole ring, pyrrolering, furan ring, thiophene ring, tetrazine ring, triazine ring,pyrazine ring, pyridazine ring, pyrimidine ring, pyridine ring,furoisoxazole ring, imidazothiazole ring, thienoisothiazole ring,thienothiazole ring, imidazopyrazole ring, cyclopentapyrazole ring,pyrrolopyrrole ring, thienothiophene ring, thiadiazolopyrimidine ring,thiazolothiazine ring, thiazolopyrimidine ring, thiazolopyridine ring,oxazolopyrimidine ring, oxazolopyridine ring, benzoxazole ring,benzisothiazole ring, benzothiazole ring, imidazopyrazine ring, purinering, pyrazolopyrimidine ring, imidazopyridine ring, benzimidazole ring,indazole ring, benzoxathiole ring, benzodioxole ring, benzodithiol ring,indolizine ring, indoline ring, isoindoline ring, furopyrimidine ring,furopyridine ring, benzofuran ring, isobenzofuran ring, thienopyrimidinering, thienopyridine ring, benzothiophene ring, cyclopentaoxazine ring,cyclopentafuran ring, benzoxazine ring, benzothiazine ring, quinazolinering, naphthyridine ring, quinoline ring, isoquinoline ring, benzopyranring, pyridopyridazine ring and pyridopyrimidine ring. Preferred aredivalent heterocyclic groups of piperazine ring, piperidine ring,pyridine ring, benzoxazole ring, benzisothiazole ring, benzothiazolering and benzimidazole ring.

“Alkoxycarbonyl” is linear or branched alkoxycarbonyl having 2 to 7carbon atoms, which is exemplified by methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl,hexyloxycarbonyl, isohexyloxycarbonyl and neohexyloxycarbonyl, withpreference given to linear or branched alkoxycarbonyl having 2 to 5carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl and tert-butoxycarbonyl.

“Lower alkoxycarbonyl” is linear or branched alkoxycarbonyl having 2 to5 carbon atoms, which is exemplified by methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl and tert-butoxycarbonyl, with preference given tomethoxycarbonyl and ethoxycarbonyl.

“Acyl” specifically means, for example, formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, capropyl,isocaproyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl,benzoyl, naphthoyl, toluoyl, hydroatropoyl, atropoyl, cinnamoyl, furoyl,glyceroyl, tropoyl, benziloyl, salicyloyl, anisoyl, vanilloyl,veratroyl, piperonyloyl, protocatechuoyl or galloyl, with preferencegiven to formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, benzoyl and naphthoyl.

“Acyloxy” is that having the above-mentioned acyl, which is exemplifiedby formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy,valeryloxy, isovaleryloxy, pivaloyloxy, caproyloxy, isocaproyloxy,acryloyloxy, propioloyloxy, methacryloyloxy, crotonoyloxy,isocrotonoyloxy, benzoyloxy, naphthoyloxy, toluoyloxy, hydroatropoyloxy,atropolyloxy, ainnamoyloxy, furoyloxy, glyceroyloxy, tropoyloxy,benziloyloxy, salicyloyloxy, anisoyloxy, vanilloyloxy, veratroyloxy,piperonyloyloxy, protocatechuoyloxy and galloyloxy, with preferencegiven to formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy,valeryloxy, isovaleryloxy, pivaloyloxy, benzoyloxy and naphthoyloxy.

“Heterocyclic group having one or more hetero atom(s) selected from thegroup consisting of a nitrogen atom, sulfur atom and oxygen atom” at R⁶is 3- to 7-membered heterocyclic group having one or more hetero atom(s)selected from the group consisting of a nitrogen atom, sulfur atom andoxygen atom, which is exemplified by aziridinyl, oxiranyl, azetyl,azetidinyl, oxetanyl, thiatriazolyl, tetrazolyl, dithiazolyl,oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, isooxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, dioxolanyl, pyrrolyl, pyrrolidinyl,furanyl, thienyl, tetrazinyl, dithiadiazinyl, thiadiazinyl, triazinyl,morpholinyl, morpholino, oxazinyl, thiazinyl, piperazinyl, pyrazinyl,pyridazinyl, pyrimidinyl, piperidyl, piperidino, pyridyl, pyranyl,thiopyranyl, dioxazepinyl, diazepinyl and azepinyl. Preferred is 5- or6-membered heterocyclic group, which is exemplified by thiatriazolyl,tetrazolyl, dithiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl,isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, dioxolanyl,pyrrolyl, pyrrolidinyl, furanyl, thienyl, tetrazinyl, dithiadiazinyl,thiadiazinyl, triazinyl, morpholinyl, morpholino, oxazinyl, thiazinyl,piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidyl, piperidino,pyridyl, pyranyl and thiopyranyl. Particularly preferred are pyrrolyl,furanyl, thienyl, piperazinyl, piperidyl, piperidino and pyridyl.

“Aromatic heterocyclic group having one or more hetero atom(s) selectedfrom the group consisting of a nitrogen atom, sulfur atom and oxygen” is5- or 6-membered aromatic heterocyclic group having one or more heteroatom(s) selected from the group consisting of a nitrogen atom, sulfuratom and oxygen atom, which is exemplified by tetrazolyl, oxadiazolyl,thiadiazolyl, triazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, pyrrolyl, furanyl, thienyl, tetrazinyl,triazinyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyridyl. Preferred is5-membered aromatic heterocyclic group, which is exemplified bytetrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, isooxazolyl,thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl andthienyl. Particularly preferred are oxadiazolyl, thiadiazolyl andtriazolyl.

“Alkoxyalkoxy” is that wherein linear or branched alkoxy having 1 to 6carbon atoms has been substituted by linear or branched alkoxy having 1to 6 carbon atoms, and is exemplified by methoxymethoxy, ethoxymethoxy,propoxymethyl, isopropoxymethoxy, butoxymethoxy, isobutoxymethoxy,sec-butoxymethoxy, tert-butoxymethoxy, pentyloxymethoxy,isopentyloxymethoxy, neopentyloxymethoxy, tert-pentyloxymethoxy,hexyloxymethoxy, isohexyloxymethoxy, neohexyloxymethoxy,tert-hexyl-oxymmthoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy,isopropoxyethoxy, butoxyethoxy, isobutoxyethoxy, sec-butoxyethoxy,tert-butoxy-ethoxy, pentyloxyethoxy, isopentyloxyethoxy,neopentyloxyethoxy, tert-pentyloxyethoxy, hexyloxyethoxy,isohexyloxyethoxy, neohexyloxyethoxy, tert-hexyloxyethoxy,methoxypropoxy, ethoxypropoxy, propoxypropoxy, isopropoxypropoxy,butoxypropoxy, isobutoxypropoxy, sec-butoxypropoxy, tert-butoxypropoxy,pentyloxypropoxy, isopentyloxypropoxy, neopentyloxypropoxy,tert-pentyloxypropoxy, hexyloxypropoxy, isohexyloxypropoxy,neohexyloxypropoxy, tert-hexyloxypropoxy, methoxybutoxy, ethoxybutoxy,propoxybutoxy, isopropoxybutoxy, butoxybutoxy, isobutoxybutoxy,sec-butoxybutoxy, tert-butoxybutoxy, pentyloxybutoxy,isopentyloxybutoxy, neopentyloxybutoxy, tert-pentyloxybutoxy,hexyloxybutoxy, isohexyloxy-butoxy, neohexyloxybutoxy,tert-hexyloxybutoxy, methoxypentyloxy, ethoxypentyloxy,propoxypentyloxy, isopropoxypentyloxy, butoxypentyloxy,isobutoxypentyloxy, sec-butoxypentyloxy, tert-butoxypentyloxy,pentyloxypentyloxy, isopentyloxypentyloxy, neopentyloxypentyloxy,tert-pentyloxypentyloxy, hexyloxypentyloxy, isohexyloxypentyloxy,neo-hexyloxypentyloxy, tert-hexyloxypentyloxy, methoxyhexyloxy,ethoxy-hexyloxy, propoxyhexyloxy, isopropoxyhexyloxy, butoxyhexyloxy,iso-butoxyhexyloxy, sec-butoxyhexyloxy, tert-butoxyhexyloxy,pentyloxy-hexyloxy, isopentyloxyhexyloxy, neopentyloxyhexyloxy,tert-pentyloxy-hexyloxy, hexyloxyhexyloxy, isohexyloxyhexyloxy,neohexyloxyhexyloxy and tert-hexyloxyhexyloxy. Preferred is that whereinlinear or branched alkoxy having 1 to 4 carbon atoms has beensubstituted by linear or branched alkoxy having 1 to 4 carbon atoms, andis exemplified by methoxymethoxy, ethoxymethoxy, propoxymethoxy,isopropoxymethoxy, butoxymethoxy, isobutoxymethoxy, sec-butoxymethoxy,tert-butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy,isopropoxyethoxy, butoxy-ethoxy, isobutoxyethoxy, sec-butoxyethoxy,tert-butoxyethoxy, methoxy-propoxy, ethoxypropoxy, propoxypropoxy,isopropoxypropoxy, butoxy-propoxy, isobutoxypropoxy, sec-butoxypropoxy,tert-butoxypropoxy, methoxybutoxy, ethoxybutoxy, propoxybutoxy,isopropoxybutoxy, butoxybutoxy, isobutoxybutoxy, sec-butoxybutoxy andtert-butoxybutoxy.

“Lower alkoxy lower alkoxy” is that wherein linear or branched alkoxyhaving 1 to 4 carbon atoms has been substituted by linear or branchedalkoxy having 1 to 4 carbon atoms, and is exemplified by methoxymethoxy,ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, butoxymethoxy,isobutoxymethoxy, sec-butoxymethoxy, tert-butoxymethoxy, methoxyethoxy,ethoxyethoxy, propoxyethoxy, isopropoxyethoxy, butoxyethoxy,isobutoxyethoxy, sec-butoxyethoxy, tert-butoxyethoxy, methoxypropoxy,ethoxypropoxy, propoxypropoxy, isopropoxypropoxy, butoxypropoxy,isobutoxypropoxy, sec-butoxypropoxy, tert-butoxypropoxy, methoxybutoxy,ethoxybutoxy, propoxybutoxy, isopropoxybutoxy, butoxybutoxy,isobutoxybutoxy, sec-butoxybutoxy and tert-butoxybutoxy, with preferencegiven to methoxymethoxy, ethoxymethoxy, methoxyethoxy and ethoxyethoxy.

“Heterocyclic group having one or more hetero atom(s) selected from thegroup consisting of an nitrogen atom, sulfur atom and oxygen” at R¹²means 3- to 7-membered heterocyclic group having one or more heteroatom(s) selected from the group consisting of a nitrogen atom, sulfuratom and oxygen, and is exemplified by aziridinyl, oxiranyl, azetyl,azetidinyl, oxetanyl, thiatriazolyl, tetrazolyl, dithiazolyl,oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, isooxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, dioxolanyl, pyrrolyl, pyrrolidinyl,furanyl, thienyl, tetrazinyl, dithiadiazinyl, thiadiazinyl, triazinyl,morpholinyl, morpholino, oxazinyl, thiazinyl, piperazinyl, pyrazinyl,pyridazinyl, pyrimidinyl, piperidyl, piperidino, pyridyl, pyranyl,thiopyranyl, dioxazepinyl, diazepinyl and azepinyl. Preferred is 5- or6-membered heterocyclic group, such as thiatriazolyl, tetrazolyl,dithiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl,isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, dioxolanyl,pyrrolyl, pyrrolidinyl, furanyl, thienyl, tetrazinyl, dithiadiazinyl,thiadiazinyl, triazinyl, morpholinyl, morpholino, oxazinyl, thiazinyl,piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidyl, piperidino,pyridyl, pyranyl and thiopyranyl. Particularly preferred are pyrrolyl,piperazinyl, piperidyl, piperidino and pyridyl.

“Alkenyl” is linear or branched alkenyl having 2 to 6 carbon atoms,which is exemplified by allyl, vinyl, propenyl, isopropenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-methyl-1-butenyl, crotyl,1-methyl-3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 1-methyl-2-pentenyl,4-pentenyl, 1-hexenyl, 3-hexenyl and 4-hexenyl.

“Alkynyl” is linear or branched alkynyl having 2 to 6 carbon atoms,which is exemplified by propargyl, 2-butynyl, 1-methyl-2-butynyl,2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 1-hexynyl and5hexynyl.

“Cycloalkylideneamino” specifically means cyclopropylideneamino,cyclobutylideneamino, cyclopentylideneamino, cyclohexylideneamino andcycloheptylideneamino, with preference given to cyclopentylidene andcyclohexylideneamino.

“Alkoxy” of the substituted alkoxy at R is linear or branched alkoxyhaving 1 to 6 carbon atoms, which is exemplified by methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy,iso-hexyloxy and neohexyloxy, with preference given to linear alkoxy,such as methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy.Particularly preferred is linear alkoxy having 1 to 4 carbon atoms,which is exemplified by methoxy, ethoxy, propoxy and butoxy.

“Alkylthio” of the substituted alkylthio at R is linear or branchedalkylthio having 1 to 6 carbon atoms, which is exemplified bymethylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio,neopentylthio, tert-pentylthio, hexylthio, isohexylthio andneohexylthio, with preference given to linear alkylthio such asmethylthio, ethylthio, propylthio, butylthio, pentylthio and hexylthio.Particularly preferred is linear alkylthio having 1 to 4 carbon atoms,which is exemplified by methylthio, ethylthio, propylthio and butylthio.

“Optionally substituted” of “optionally substituted non-aromaticheterocyclic group containing nitrogen” means that the group may besubstituted by 1 to 3 substituent(s) and said substituents may be thesame or different. The position of the substituent(s) is optional and isnot particularly limited. Specific examples of the substituents includethe above-mentioned lower alkyl, the above-mentioned halogenated loweralkyl, the above-mentioned cycloalkyl, the above-mentioned aralkyl, theabove-mentioned aryl, and the above-mentioned amino-protecting group.Preferred are lower alkyl and amino-protecting group.

“Optionally substituted” of “optionally substituted linear or branchedalkylene which may have one or more double bond(s) or triple bond(s) inthe chain” means that the group may be substituted by one or moresubstituent(s). Examples of the substituents include the above-mentionedhalogen atom, hydroxy, amino which may be substituted by a substituentselected from the group consisting of the above-mentioned lower alkyl,the above-mentioned halogenated lower alkyl, the above-mentionedcycloalkyl, the above-mentioned aralkyl, the above-mentioned aryl andthe above-mentioned amino protecting group, the above-mentioned loweralkoxy, the above-mentioned aralkyl and the above-mentioned cycloalkyl.

“Optionally substituted” of “optionally substituted alkoxy” and“optionally substituted alkylthio” at R¹¹ means that the group may besubstituted by one or more substituent(s), and said substituents may bethe same or different. The position of the substituent(s) is optionaland is not particularly limited. Specific examples of the substituentsinclude the above-mentioned halogen atom, the above-mentioned loweralkoxy, the above-mentioned alkylthio, amino which may be substituted bythe above-mentioned lower alkyl or the above-mentioned acyl, carboxy,the above-mentioned alkoxycarbonyl, the above-mentioned acyl, theabove-mentioned acyloxy, the above-mentioned aryl, the above-mentionedaryloxy, the above-mentioned arylthio, the above-mentionedaryloxycarbonyl, the above-mentioned aralkyloxy, and the above-mentionedaralkyloxycarbonyl. Preferred are amino, lower alkoxy, halogen atom,carboxy, alkoxycarbonyl and aralkyloxycarbonyl.

“Optionally substituted” of “optionally substituted aryl” “optionallysubstituted cycloalkyl”, “optionally substituted aryloxy”, “optionallysubstituted aralkyloxy” and “optionally substituted arylthio” at R¹¹means that they have 1 to 3 substituent(s) on the ring wherein saidsubstituents may be the same or different. The position of thesubstituent(s) is optional and is not particularly limited. Specificexamples of the substituents include the above-mentioned lower alkyl,the above-mentioned halogen atom, the above-mentioned lower alkoxy, theabove-mentioned alkylthio, amino which may be substituted by theabove-mentioned lower alkyl or the above-mentioned acyl, carboxy, theabove-mentioned alkoxycarbonyl, the above-mentioned acyl, theabove-mentioned acyloxy, the above-mentioned aryl, the above-mentionedaryloxy, the above-mentioned arylthio, the above-mentionedaryloxycarbonyl, the above-mentioned aralkyloxy and the above-mentionedaralkyloxycarbonyl. Preferred are lower alkyl, amino, lower alkoxy,halogen atom, carboxy, alkoxycarbonyl and aralkyloxycarbonyl.Particularly preferred is lower alkyl.

“Optionally substituted” of “optionally substituted aralkyl” at R⁵ meansthat it may have 1 to 3 substituent(s) on aryl wherein said substituentsmay be the same or different. The position of the substituent(s) isoptional and is not particularly limited. Specific examples of thesubstituents include the above-mentioned lower alkyl, theabove-mentioned lower alkoxy, the above-mentioned acyl, amino which maybe substituted by the above-mentioned lower alkyl or the above-mentionedacyl, the above-mentioned alkoxycarbonyl, the above-mentionedaryloxycarbonyl, the above-mentioned aryloxy, the above-mentionedalkylthio, the above-mentioned arylthio, the above-mentioned aryl, andthe above-mentioned halogen atom. Preferred are lower alkyl, loweralkoxy and halogen atom. Particularly preferred is lower alkyl.“Optionally substituted” of “optionally substituted lower alkyl”,“optionally substituted lower alkoxy” and “optionally substituted loweralkylthio” at R⁶ means that the group may be substituted by one or moresubstituent(s) and said substituents may be the same or different. Theposition of the substituent(s) is optional and is not particularlylimited. Specific examples of the substituents include theabove-mentioned halogen atom, hydroxy, the above-mentioned alkoxy, theabove-mentioned aryloxy, amino which may be substituted by theabove-mentioned lower alkyl or the above-mentioned acyl, mercapto, theabove-mentioned alkylthio, the above-mentioned arylthio, carboxy, theabove-mentioned alkoxycarbonyl, the above-mentioned aryloxycarbonyl,carbamoyl, the above-mentioned halogenated lower alkyl, sulfamoyl,cyano, nitro, alkylsulfonyl such as methylsulfonyl, ethylsulfonyl,isopropylsulfonyl, alkylsulfinyl such as methylsulfinyl, ethylsulfinyland isopropylsulfinyl, and arylsulfonyl such as phenylsulfonyl.Preferred are halogen atom, hydroxy, alkoxy, amino, carboxy andalkoxycarbonyl.

“Optionally substituted” of “optionally substituted aryl”, “optionallysubstituted cycloalkyl” and “optionally substituted heterocyclic grouphaving one or more hetero atom(s) selected from the group consisting ofa nitrogen atom, sulfur atom and oxygen atom” at R⁶ means that the groupmay be substituted by one or more substituent(s) and said substituentsmay be the same or different. The position of the substituent(s) isoptional and is not particularly limited. Specific examples of thesubstituents include the above-mentioned lower alkyl, theabove-mentioned halogen atom, hydroxy, the above-mentioned alkoxy, theabove-mentioned aryloxy, amino which may be substituted by theabove-mentioned lower alkyl or the above-mentioned acyl, mercapto, theabove-mentioned alkylthio, the above-mentioned arylthio, carboxy, theabove-mentioned alkoxycarbonyl, the above-mentioned aryloxycarbonyl,carbamoyl, the above-mentioned halogenated lower alkyl, sulfamoyl,cyano, nitro, alkylsulfonyl such as methylsulfonyl, ethylsulfonyl andisopropylsulfonyl, alkylsulfinyl such as methylsulfinyl, ethylsulfinyland isopropylsulfinyl, and arylsulfonyl such as phenylsulfonyl.Preferred are lower alkyl, halogen atom, hydroxy, alkoxy, amino, carboxyand alkoxycarbonyl.

“Optionally substituted” and “optionally substituted alkyl” at R⁷ meansthat the group may be substituted by one or more substituent(s) and saidsubstituent(s) may be the same or different. The position of thesubstituent(s) is optional and is not particularly limited. Specificexamples of the substituents include hydroxy, the above-mentioned loweralkoxy, mercapto, the above-mentioned lower alkylthio, carboxy, theabove-mentioned lower alkoxycarbonyl, halogen atom, and amino which maybe substituted by the above-mentioned lower alkyl or the above-mentionedacyl. Preferred are hydroxy, halogen atom and lower alkoxy.

“Optionally substituted” of “optionally substituted aryl” and“optionally substituted aromatic heterocyclic group having one or morehetero atom(s) selected from the group consisting of a nitrogen atom,sulfur atom and oxygen atom” at R⁷ means that they may have 1 to 3substituent(s) on the ring wherein said substituents may be the same ordifferent. The position of the substituent(s) is optional and is notparticularly limited. Specific examples of the substituents include theabove-mentioned lower alkyl, hydroxy, the above-mentioned lower alkoxy,mercapto, the above-mentioned lower alkylthio, carboxy, theabove-mentioned lower alkoxycarbonyl, halogen atom, and amino which maybe substituted by the above-mentioned lower alkyl or the above-mentionedacyl. Preferred are hydroxy, lower alkyl, halogen atom and lower alkoxy.

“Optionally substituted” of “optionally substituted alkenyl” and“optionally substituted alkynyl” at R¹² means that the group may besubstituted by one or more substituent(s) and said substituent(s) may bethe same or different. The position of the substituent(s) is optionaland is not particularly limited. Specific examples of the substituentsinclude hydroxy, the above-mentioned alkoxy, carboxy, theabove-mentioned alkoxycarbonyl, the above-mentioned acyloxy, and aminowhich may be substituted by the above-mentioned alkyl, theabove-mentioned aryl, the above-mentioned aralkyl or the above-mentionedamino-protecting group. Preferred are hydroxy, alkoxy, carboxy,alkoxycarbonyl and acyloxy.

“Optionally substituted” of “optionally substituted cycloalkyl”,“optionally substituted aryl” and “optionally substituted heterocyclicgroup having one or more hetero atom(s) selected from the groupconsisting of a nitrogen atom, sulfur atom and oxygen atom” at R¹² meansthat they may have 1 to 3 substituent(s) on the ring wherein saidsubstituents may be the same or different. The position of thesubstituent(s) is optional and is not particularly limited. Specificexamples of the substituents include hydroxy, the above-mentioned loweralkoxy, mercapto, the above-mentioned lower alkylthio, carboxy, theabove-mentioned lower alkoxycarbonyl, the above-mentioned lower alkyl,amino which may be substituted by the above-mentioned lower alkyl, theabove-mentioned halogen atom, carbamoyl, cyano, the above-mentionedacyl, nitro, sulfamoyl, alkoxythiocarbonyl, thioalkanoyl, alkylsulfonylsuch as methylsulfonyl and ethylsulfonyl, azomethine which may besubstituted by the above-mentioned lower alkyl, the above-mentioned arylor the above-mentioned aralkyl, alkoxyamino such as methoxyamino andisopropoxyamino, hydrazino which may be substituted by theabove-mentioned lower alkyl, the above-mentioned aryl or theabove-mentioned aralkyl, aminooxy which may be substituted by theabove-mentioned lower alkyl, the above-mentioned aryl or theabove-mentioned aralkyl, and alkylsulfinyl such as methylsulfinyl.Preferred are hydroxy, lower alkyl, halogen atom, lower alkoxy, aminoand carboxy.

“Optionally substituted” of “optionally substituted aralkyl” at R¹²means that it may have 1 to 3 substituent(s) on aryl wherein saidsubstituents may be the same or different. The position of thesubstituent(s) is optional and is not particularly limited. Specificexamples of the substituents include the above-mentioned lower alkyl,the above-mentioned lower alkoxy, the above-mentioned acyl, amino whichmay be substituted by the above-mentioned lower alkyl or theabove-mentioned acyl, the above-mentioned alkoxycarbonyl, theabove-mentioned aryloxycarbonyl, the above-mentioned aryloxy, theabove-mentioned alkylthio, the above-mentioned arylthio, theabove-mentioned aryl, and the above-mentioned halogen atom. Preferredare lower alkyl, lower alkoxy and halogen atom.

The compounds of the present invention which is shown by the formula (I)can be synthesized by, for example, the following method, to which thesynthesis method of the compounds of the present invention is notlimited.

 wherein

-   R′ is R protected by hydroxy-protecting group or amino-protecting    group, which is more specifically protected R_(a), protected alkoxy    substituted by R_(a), protected alkylthio substituted by R_(a),    protected alkylamino substituted by R_(a), protected and optionally    substituted non-aromatic heterocyclic group containing nitrogen, or    protected hydroxy,    -   wherein when R is dimethylamino, N-methylpiperazinyl or        N-methylpiperidyl, R′ means R itself, since R does not need to        be protected,    -   wherein R_(a) is amino, guanidino, amidino, carbamoyl, ureido,        thioureido, hydrazino, hydrazinocarbonyl or imino, these groups        being optionally substituted by a substituent selected from the        group consisting of lower alkyl, halogenated lower alkyl,        cycloalkyl, aralkyl, aryl and amino-protecting group;-   R¹⁴ is carboxy-protecting group such as methyl, ethyl, tert-butyl,    allyl, phenyl, benzyl, trichloroethyl, p-nitrobenzyl,    trimethyl-silyl, tert-butyldimethylsilyl, methoxymethyl and    2-trimethyl-silylethyl;-   W is halogen atom;-   A′ is A without one end methylene;-   Z is hydrogen atom or substituent which activates X such as    triphenylphosphonium, triphenylphosphonate and aryl-sulfonyl; and A,    X, M, m, R, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above.    (Step 1)

The compound (VI) can be synthesized by reacting compound (II) andcompound (III) in the presence of a combined condensing agent oftriphenylphosphine, trimethylphosphine, triethylphosphine, triphenylphosphite, trimethyl phosphite, triethyl phosphite, and the like, anddiisopropyl azodicarboxylate, diethyl azodicarboxylate, dicyclohexylazodicarboxylate and the like, in an organic solvent such as ether,tetrahydrofuran, dioxane, dichloromethane, chloroform, benzene, tolueneand dimethylformamide, or a mixed solvent thereof, under ice-cooling tounder heating.

This method is particularly preferable when X is oxygen atom or sulfuratom.

The compound (VI) can be also synthesized by the following method.

(Step 2)

The compound (VI) can be synthesized by reacting compound (IV) andcompound (III) in the presence of a base such as sodium hydride,potassium hydride, lithium hydride, potassium carbonate, sodiumcarbonate, potassium tert-butoxide, lithium diisopropylamide,methyllithium, n-butyllithium, sec-butyllithium and tert-butyllithium,in an organic solvent such as dimethylformamide, methylene chloride,tetrahydrofuran, ether, benzene and toluene, or a mixed solvent thereof,at a temperature of from −78° C. to under heating.

This method is particularly preferable when X is sulfur atom or oxygenatom.

When X is —SO— or —SO₂—, the corresponding sulfide obtained in the aboveStep 1 or Step 2 is oxidized with an oxidizing agent such as hydrogenperoxide, peracetic acid, metaperiodate, metachloroperbenzoic acid, acylnitrate and dinitrogen tetraoxide, to synthesize compound (VI).

The compound (VI) wherein X is particularly —NR⁸— or —CR⁹R¹⁰— can bealso synthesized by the following method.

(Step 3)

The compound (VI) can be synthesized by condensing compound (V) andcompound (III) in the presence of a suitable base (e.g., lithiumdiisopropylamide, lithium bis (trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide, n-butyllithium, potassium tert-butoxide,sodium hydroxide, potassium hydroxide, sodium hydride and potassiumhydride) as necessary, in water or an organic solvent such as methanol,ethanol, dimethylformamide, ether, dioxane, tetrahydrofuran, ethylacetate, diisopropyl ether, dimethoxyethane, toluene, hexane anddimethyl sulfoxide, or a mixed solvent thereof, and subjecting theobtained compound to catalytic reduction using hydrogen gas in thepresence of a metallic catalyst such as platinum black, platinum oxide,palladium black, palladium oxide, palladium hydroxide, palladium carbonand Raney nickel, or treating the compound with a reducing agent such assodium borohydride, sodium cyanoborohydride, trimethylsilane,triethylsilane, alkali metal-ammonia, alkali metal-ethylamine, sodiumamalgam and potassium amalgam.

The compound (I) can be synthesized by subjecting compound (VI) obtainedin the above Step 1, 2 or 3 to the following Steps 4-6.

(Step 4)

The compound (VII) can be synthesized by reacting compound (VI) in thepresence of a hydroxide or carbonate of alkali metal such as sodium,potassium and lithium, or a base such as1,5-diazabicyclo[4.3.0]non-5-ene and 1,8-diazabicyclo[5.4.0]undec-7-ene,or an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid,hydrogen chloride, hydrogen bromide, hydrogen fluoride, acetic acid andtrifluoroacetic acid, in water or an organic solvent such as methanol,ethanol, dichloromethane, chloroform, tetrahydrofuran, toluene andxylene or a mixed solvent thereof, under ice-cooling to under heating,or by subjecting compound (VI) to catalytic reduction using hydrogen gasin an organic solvent such as methanol, ethanol, dimethylformamide,ether, dioxane, tetrahydrofuran and acetic acid or a mixed solventthereof, in the presence of a metallic catalyst such as platinum black,platinum oxide, palladium black, palladium oxide, palladium carbon andRaney nickel, or by reacting compound (VI) in the presence of quaternaryammonium fluoride such as tetraethylammonium fluoride andtetra-n-butylammonium fluoride, in an organic solvent such astetrahydrofuran, dimethylformamide and dimethyl sulfoxide or a mixedsolvent thereof, under ice-cooling to under heating.

(Step 5)

The compound (I′) can be synthesized by reacting compound (VII) andcompound (VIII) using a condensing agent such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl)dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA) andcarbonyldiimidazole (CDI), in the presence of an activating agent suchas 1-hydroxybenzotriazole (HOBT), hydroxysuccinimide (HOSu) andN-hydroxy-5-norbornene-2,3-dicarboximide (HONB) as necessary, in anorganic solvent such as dimethylformamide, dichloromethane, chloroform,acetonitrile, tetrahydrofuran, dimethyl sulfoxide, carbon tetrachlorideand toluene or a mixed solvent thereof, under ice-cooling to underheating. When compound (VIII) is, for example, hydrochloride, thisreaction can be carried out in the presence of a base such astriethylamine, N-methylmorpholine and 4-dimethylaminopyridine. When R⁷is a group having hydroxy, such as —CONHOH and —CH₂OH, compound (VIII)wherein said hydroxy is protected in advance is used.

(Step 6)

This step aims at eliminating the hydroxy-protecting group oramino-protecting group at R′, and can be carried out according to asuitable known method. For example, when the amino-protecting group atR′ is Boc (tert-butoxycarbonyl group), compound (I′) is reacted in thepresence of an acid such as hydrochloric acid, hydrobromic acid,trifluoroacetic acid, p-toluenesulfonic acid, methane-sulfonic acid,hydrogen chloride-dioxane, hydrogen chloride-ether and hydrogenchloride-ethyl acetate, in water or an organic solvent such as dioxane,ether, dichloromethane, tetrahydrofuran, methanol, ethanol, chloroform,benzene, toluene and ethyl acetate or a mixed solvent thereof or withoutsolvent, to give compound (I). When the amino protecting group is, forexample, benzyloxycarbonyl group, compound (I) can be synthesized bycatalytic hydrogenation using hydrogen gas in water or an organicsolvent such as methanol, ethanol, dimethylformamide, ether, dioxane,tetrahydrofuran and acetic acid or a mixed solvent thereof, in thepresence of a metallic catalyst such as palladium carbon, platinum oxideand Raney nickel. When R′ is hydroxy protected by hydroxy-protectinggroup, compound (I) can be synthesized by a conventional method such ascatalytic hydrogenation. When R⁷ is protected at hydroxy, thehydroxy-protecting group is eliminated by a conventional method such ascatalytic hydrogenation, and thereafter or simultaneously therewith, theabove Step is carried out.

The compound (I) wherein R⁷ is carboxyl group can be synthesized by, forexample, subjecting compound (I′) wherein R⁷ is tert-butoxy-carbonylgroup or benzyloxycarbonyl group to the above-mentioned reaction.

 wherein

-   W¹ is —COW³, —SO₂W³ or —O—COW³    -   wherein W³ is hydroxy or halogen atom;-   W² is hydroxy, mercapto or —NR⁸H    -   wherein R⁸ is as defined above; and-   A, X, M, R¹, R¹, R², R³, R⁴ and R¹⁴ are as defined above.

The compound (VI) wherein X is —COO—, —CONR⁸—, —SO₂NR⁸—, —COS—,—OOC—NR⁸— or —O—CO—O—can be also synthesized by the following method.

(Step 7)

The compound (VI) can be synthesized by reacting compound (IX) andcompound (X) using a condensing agent such as WSC.HCl, DCC, DPPA andCDl, in the presence of an activating agent such as HOBT, HOSu and HONBas necessary, in an organic solvent such as dimethylformamide,dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethylsulfoxide, carbon tetrachloride and toluene or a mixed solvent thereof,under ice-cooling to under heating (this reaction can be carried out inthe presence of a base such as triethylamine, N-methylmorpholine,pyridine, 4-dimethylaminopyridine and N-methylpiperidine), or in thepresence of a hydroxide or carbonate of alkali metal such as sodium,potassium and lithium, or a base such as triethylamine, pyridine,N-methylmorpholine, N-methylpiperidine and 4-dimethylaminopyridine, inwater or an organic solvent such as dimethylformamide, dichloromethane,chloroform, tetrahydrofuran, dimethyl sulfoxide, benzene and toluene ora mixed solvent thereof, under ice-cooling to under heating.

The compound (VI) wherein X is —OOC—, —NR⁸CO—, —NR⁸SO₂— or —NR⁸—COO— canbe also synthesized by the following method.

(Step 8)

The compound (VI) can be synthesized using compound (XI) and compound(XII) according to the method of the above-mentioned Step 7.

When X is a divalent aromatic heterocyclic group having one or morehetero atoms selected from nitrogen atom, sulfur atom and oxygen atom,such as divalent oxadiazole ring, compound (VI) can be also synthesizedby the following method.

 wherein A, M, R′, R¹, R², R³, R⁴ and R¹⁴ are as defined above.(Step 9)

The compound (XV) can be synthesized by reacting compound (XIII) andcompound (XIV) using a condensing agent such as WSC.HCl, DCC, DPPA andCDI, in the presence of an activating agent such as HOBT, HOSu and HONBas necessary, in an organic solvent such as dimethylformamide,dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethylsulfoxide, carbon tetrachloride and toluene or a mixed solvent thereof,under ice-cooling to under heating. This reaction can be carried out inthe presence of a base such as trimethylamine, N-methylmorpholine,pyridine, 4-dimethylaminopyridine and N-methylpiperidine.

(Step 10)

The compound (VI′) can be synthesized by heating compound (XV) in anorganic solvent such as toluene, dioxane, tetrahydrofuran, benzene andxylene, or a mixed solvent thereof.

The compound (I) can be synthesized by treating compound (VI) andcompound (VI′) obtained in the above Steps 7, 8 and 10 by the samemethod as the above Steps 4-6.

When at least one R¹, R², R³ and R⁴ of compound (I) is a halogen atom,compound (I) can be also synthesized by the following method.

 wherein

-   -   R^(1′), R^(2′), R^(3′) and R^(4′)are the same or different and        each is hydrogen atom, hydroxy, alkoxy, mercapto, alkylthio,        nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, acyl,        alkyl which may be substituted by a substituent selected from        hydroxy, lower alkoxy and halogen atom, amino which may be        substituted by a substituent selected from alkyl, aryl, aralkyl        and amino-protecting group, or —CO—R¹¹        -   wherein R¹¹ is as defined above,

provided that at least one of them is hydrogen atom; and A, X, M, m,R′,R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above.

(Step 11)

The compound (I′) can be synthesized by reacting compound (III) in thepresence of a halogenating agent such as tert-butyl hypochlorite,tert-butyl hypobromite, tert-butyl hypoiodite, sulfuryl chloride,sulfuryl bromide, thionyl chloride, thionyl bromide, fluorine, chlorine,bromine, iodine, hydrogen fluoride, silver difluoride and xenondifluoride, in an organic solvent such as dichloromethane, chloroform,acetonitrile, toluene, benzene, ether, tetrahydrofuran, dioxane,methanol, ethanol, carbon tetra-chloride and ethyl acetate, or a mixedsolvent thereof, or without solvent, under ice-cooling to under heating.When the protective group is removed by this step, a re-protection isapplied. In the case of Boc, for example, the compound is protected withdi-tert-butyl dicarbonate and the like in the presence of a suitablebase such as triethylamine and pyridine.

The compound (I) can be synthesized by treating the obtained compound(I′) by the same method as in the above Step 6.

The above Step 11 may be carried out after synthesizing compound (VI)corresponding to compound (III). The subsequent same treatment as in theabove Steps 4-6 gives compound (I).

The compound (I) wherein at least one of R¹, R², R³ and R⁴ is —O—CO—R¹¹can be also synthesized by the following method.

 wherein

-   -   R¹″, R²″, R³″ and R⁴″ are the same or different and each is        hydrogen atom, hydroxy, halogen atom, alkoxy, mercapto,        alkylthio, nitro, cyano, carboxy, alkoxycarbonyl,        aryloxycarbonyl, acyl, alkyl, which may be substituted by a        substituent selected from hydroxy, lower alkoxy and halogen        atom, or amino which may be substituted by a substituent        selected from alkyl, aryl, aralkyl and amino-protecting group,        wherein at least one of them is hydroxy; and    -   A, X, M, m, W, R′,R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R¹¹ are as        defined above.        (Step 12)

The compound (I′) can be synthesized by reacting compound (I′″) withcompound (XVI) in an organic solvent such as dichloromethane,chloroform, ether, tetrahydrofuran, dioxane, benzene, toluene,dimethylformamide, ethyl acetate and acetonitrile or a mixed solventthereof, in the presence of a base such as pyridine, triethylamine,N-methylmorpholine, N-methylpiperidine and 4-dimethylaminopyridine.

The compound (I) can be synthesized by reacting the obtained compound(I′) by the same method as in the above Step 6.

The compound of the formula (I) of the present invention can be alsosynthesized by the following synthetic method.

 wherein A, A′, X, M, m, W, Z, R′, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are asdefined above.(Step 13)

The compound (XVII) can be synthesized by subjecting compound (III′) andcompound (VIII) to the same reaction as in the above Step 5.

(Step 14)

The compound (I′) can be synthesized by subjecting compound (II) andcompound (XVII) to the same reaction as in the above Step 1.

The compound (I′) can be also synthesized by the following method.

(Step 15)

The compound (I′) can be synthesized by subjecting compound (IV) andcompound (XVII) to the same reaction as in the above Step 2.

The compound (I′) wherein S is —NR⁸— or —CR⁹R¹⁰— can be also synthesizedby the following method.

(Step 16)

The compound (I′) can be synthesized by subjecting compound (V) andcompound (XVII) to the same reaction as in the above Step 3.

The compound (I) can be synthesized by subjecting compound (I′) obtainedin the above Steps 14-16 to the same reaction as in the above Step 6.

The compound (I′) wherein X is —COO—, —CONR⁸—, —SO₂NR⁸—, —COS—,—OOC—NR⁸— or —O—CO—O— can be also synthesized by the following method.

 wherein A, X, M, m, W¹, W², R′, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are asdefined above.(Step 17)

The compound (XVIII) can be synthesized by subjecting compound (X′) andcompound (VIII) to the same reaction as in the above Step 5.

(Step 18)

The compound (I′) can be synthesized by subjecting compound (IX) andcompound (XVIII) to the same reaction as in the above Step 7.

The compound (I′) wherein X is —OOC—, —NR⁸CO—, —NR⁸SO₂— or —NR⁸—COO— canbe also synthesized by the following method.

 wherein A, X, M, m, W¹, W², R′, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are asdefined above.(Step 19)

The compound (XIX) can be synthesized by subjecting compound (XII′) andcompound (VIII) to the same reaction as in the above Step 5.

(Step 20)

The compound (I′) can be synthesized by subjecting compound (XI) andcompound (XIX) to the same reaction as in the above Step 8.

The compound (I) can be synthesized by subjecting compound (I′) obtainedin the above Step 18 and Step 20 to the same reaction as in the aboveStep 6.

When X is —CR⁹R¹⁰—, —CO—, —C═C— or —CS—, the following step can be usedfor synthesis.

 wherein A, A′, M, X, m, W¹, W², R′, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R¹⁴are as defined above.(Step 21)

The compound (XXI) can be synthesized by reacting the correspondingGrignard reagent (IV′) obtained from compound (IV) by a conventionalmethod, with compound (XX) in an organic solvent such as ether,tetrahydrofuran and dioxane or a mixed solvent thereof, at a temperatureof from −78° C. to under heating.

(Step 22)

The compound (VI″) can be synthesized by reacting compound (XXI) in thepresence of an oxidizing agent such as chronic anhydride, pyridiniumchlorochromate, manganese dioxide, sodium hypochorite and rutheniumtetraoxide, in an organic solvent such as ether, tetrahydrofuran anddioxane or a mixed solvent thereof, under ice-cooling to under heating.

The compound (VI″) wherein X is —CS— can be synthesized by reactingcompound (VI″) obtained by the above method, in the presence of hydrogensulfide, phosphorus pentasulfide,2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphoisphetane-2,4-disulfide(Lawsson's reagent) and the like, in an organic solvent such as benzene,toluene, methanol and ethanol or a mixed solvent thereof, underice-cooling to under heating.

(Step 23)

The compound (VI′″) can be synthesized by reacting compound (XXI) in thepresence of a reducing agent such as triethylsilane, lithium aluminumhydride-aluminum chloride, sodium borohydride-trifluoroborane, sodiumcyanoborohydride-methyl iodide and triphenylphosphonium, in an organicsolvent such as ether, tetrahydrofuran and dioxane, or a mixed solventthereof, at a temperature of from −78° C. to under heating.

(Step 24)

The compound (VI″″) can be synthesized by reacting compound (XXI) in thepresence of sulfuric acid, phosphoric acid, potassium hydrogensulfate,oxalic acid, p-toluenesulfonic acid, boron trifluoride-etherate, thionylchloride-pyridine, phosphorus oxychloride-pyridine, methanesulfonylchloride-pyridine, p-toluenesulfonyl chloride-pyridine, and the like, inan organic solvent such as ether, tetrahydrofuran and dioxane, or amixed solvent thereof, under ice-cooling to under heating.

The compound (I) can be synthesized by treating compound (VI″), (VI′″)or (VI″″) obtained in the above Steps 22-24 by the same method as in theabove Steps 4-6.

The compound of the formula (I) can be converted to a pharmaceuticallyacceptable acid addition salt by a conventional method by treating samewith an inorganic acid (e.g., hydrochloric acid, sulfuric acid,phosphoric acid, hydrobromic acid and nitric acid) or organic acid(e.g., oxalic acid maleic acid, humaric acid, malic acid, tartaric acid,succinic acid, citric acid, acetic acid, lactic acid, methanesulfonicacid, p-toluenesulfonic acid, benzoic acid, valeric acid, malonic acid,nicotinic acid and propionic acid).

The compound thus obtained can be separated and purified by a knownmethod for separation and purification, such as concentration,concentration under reduced pressure, solvent extraction, precipitation,recrystallization and chromatography.

The compound of the present invention includes one or more stereoisomersdue to an assymetric carbon, and such isomers and mixtures thereof arealso encompassed in the present invention. In addition, hydrates andsolvates with pharmaceutically acceptable organic solvents, as well asprodrugs of the compound of the present invention are also encompassedin the present invention.

The compound of the present invention shows superior effects ofsuppressing production of inflammatory cytokines in mammals such ashuman, rabbit, dog and cat, and is useful for the prophylaxis andtreatment of noninfections or infectious diseases accompanied byneutrophile infiltration, which are represented by rheumatic diseases(e.g., rheumatoid arthritis); arthritis due to gout; systemic lupuserythematosus; dermatopathy (e.g., psoriasis, pustulosis and atopicdermatitis); respiratory diseases (e.g., bronchial asthma, bronchitis,ARDS and diffused interstitial pneumonia); inflammatory enteric diseases(e.g., ulcerative colitis and Crohn's disease); acute or chronichepatitis inclusive of fulminant hepatitis; acute or chronicglomerulonephritis; nephropyelitis; uvetis caused by Behcet disease andvogt-Koyanagi Harada disease; Mediterranean fever (polyserositis);ischemic diseases (e.g., myocardial infarction); and systemiccirculatory failure and multi-organ failure caused by sepsis.

The suppresive effect of the compound of the present invention oninflammatory cytokines such as IL-6 and GM-CSF has been alsoacknowledged.

When the compound of the formula (I) of the present invention or apharmaceutically acceptable salt thereof is used as pharmaceuticalpreparation comprising same as an active ingredient, it is generallyadmixed with a pharmaceutically acceptable carrier, excipient, diluent,extender, disintegrator, stabilizer, preservative, buffer, emulsifyingagent, aromatic, coloring, sweetener, thickener, flavor, solubilizer andother additives such as water, vegetable oil, alcohols (e.g., ethanoland benzyl alcohol), polyethylene glycol, glycerol triacetate, gelatin,lactose and carbohydrate (e.g. starch), magnesium stearate, talc,lanolin, white petrolatum known Per se to give a pharmaceuticalcomposition in the form of tablet, pill, powder, granule, suppository,injection, eye drop, liquid, capsule, troche, aerosol, elixir,suspension, emulsion syrup and the like, which is administered orally orparenterally.

While the dose varies depending on the kind of severity of diseases,compound to be administered, administration route, age, sex, body weightetc. of the patients, and so on, when it is orally administered to anadult patient, for example, the daily dose is generally 0.01-1,000 mg,preferably about 0.1-100 mg, and when it is intravenously administeredto an adult patient, for example, the daily dose is generally 0.01-1,000mg, preferably about 0.05-50 mg, which is administered in one or severaldoses.

The present invention is described in more detail by illustrativePreparative Examples and Examples, to which the present invention is notlimited.

Hereunder follow Preparative Examples of the intermediate compoundsshown in Table 1.

TABLE 1 Preparative Example 1

2

3

4

5

6

7

 

PREPARATIVE EXAMPLE 1

5-Chloro-2,4-dihydroxy-3-methylbenzoic acid

To a solution of 2,4-dihydroxy-3-methylbenzoic acid methyl ester (9.9 g)in ethyl acetate (100 ml) was added tert-butyl hypochlorite (12.3 ml)under ice-cooling. After stirring for 2 hours, hexane (200 ml) wasadded, and the mixture was cooled with ice to allow precipitation ofcrystals. The crystals were collected by filtration, and dissolved in amixed solvent of methanol (20 ml) and tetrahydrofuran (THF, 20 ml). A 1Mlithium hydroxide solution (40 ml) was added to the solution, and themixture was refluxed under heating for 18 hours. The reaction mixturewas concentrated, and a 10% aqueous citric acid solution was added tothe residue, which was followed by extraction with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overanhydrous sodium sulfate. The organic layer was concentrated underreduced pressure to give the title compound (4.14 g, yield 37%).

PREPARATIVE EXAMPLE 2

Methyl 2-hydroxybenzoate-4-carboxamide oxime

To a solution of 2-hydroxy-4-cyanobenzoic acid methyl ester (2.00 g) inmethanol (30 ml) were added water (6 ml), hydroxylamine hydrochloride(1.57 g) and sodium hydrogenate (1.9 g), and the mixture was stirredwith heating at 70° C. for 3 hours. The reaction mixture wasconcentrated, diluted with a 10% aqueous citric acid solution, andfiltered. The fitrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (developingsolvent: hexane/ethyl acetate=3/2 v/v) to give the title compound (823mg, yield 35%).

PREPARATIVE EXAMPLE 3

1-tert-Butoxycarbonyl-4-ethylisonipecotic acid

(1) 1-tert-Butoxycarbonyl-4-ethylisonipecotic acid ethyl ester

To a solution of 1-tert-butoxycarbonylisonipecotic acid ethyl ester (576mg) in THF (15 ml) was added a solution of lithium diisopropyl-amide(290 mg) in THF (10 ml) in a stream of argon gas at −78° C., and thereaction mixture was stirred at the same temperature for 1 hour. Ethyliodide (0.36 ml) was added to the above solution at −78° C., and themixture was stirred for 18 hours. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed successively with 1N hydrochloric acid, water andsaturated brine, and dried over anhydrous magnesium sulfate. The organiclayer was concentrated under reduced pressure to give the title compound(585 mg, yield 92%).

(2) 1-tert-Butoxycarbonyl-4-ethylisonipecotic acid

To a solution of 1-tert-butoxycarbonyl-4-ethylisonipecotic acid ethylester (570 mg) in ethanol (10 ml) was added a 1M lithium hydroxidesolution (8 ml), and the mixture was refluxed under heating for 20hours. Then, the reaction mixture was concentrated, and water was addedto the residue. The aqueous layer was washed with ether acidified with1N hydrochloric acid, and extracted with ether. The organic layer wasdried over anhydrous magnesium sulfate, and concentrated under reducedpressure to give the title compound (233 mg, yield 45%).

PREPARATIVE EXAMPLE 4

L-Phenylalanylaminobenzene hydrochloride

To a solution of N-tert-butoxycarbonyl-L-phenylalanine hydrochloride(2.65 g) and aniline (1.02 g) in dimethylformamide (DMF, 50 ml) wereadded 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(WSC.HCl) and hydroxybenzotriazole (HOBT, 1.5 g) at room temperature,and the mixture was stirred for 6 hours. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed successively with a 10% aqueous citric acid solution,water, a saturated aqueous sodium hydrogencarbonate solution, water andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas distilled away under reduced pressure to giveN-tert-butoxycarbonyl-L-phenylalanylamino-benzene. To a solution of theobtained compound in dichloromethane (20 ml) was added trifluoroaceticacid (10 ml) at room temperature, and the mixture was stirred for 1hour. Toluene (10 ml) was added to the reaction mixture, and the mixturewas concentrated under reduced pressure. A 1M hydrogen chloride-ethersolution (10 ml) was added to the residue, and crystallization gave thetitle compound (1.45 g, yield 52%).

PREPARATIVE EXAMPLE 5

L-Phenylalanyl-O-benzylhydroxyamide hydrochloride

The title compound (2.48 g, yield 92%) was obtained in the same manneras in Preparative Example 4 above, usingN-tert-butoxycarbonyl-L-phenylalanine (2.65 g) and O-benzylhydroxylaminehydrochloride (1.60 g).

PREPARATIVE EXAMPLE 6

1-(3-Methyl-1,2,4-oxadiazol-5-yl)-2-phenylethylamine hydrochloride

To a solution of acetamide oxime [2.67 g, J. Saunders et al., J. Med.Chem., 33, 1128 (1990)] in THF (125 ml) was added 60% sodium hydride(1.44 g) in oil, and the mixture was refluxed under heating for 1 hour.Then, the reaction mixture was allowed to cool, and a solution ofN-tert-butoxycarbonyl-L-phenylalanine methyl ester (8.38 g) in THF (40ml) was added at room temperature. The mixture was refluxed underheating for 20 minutes. The mixture was allowed to cool, and water (10ml) was added, which was followed by concentration under reducedpressure. A 10% aqueous citric acid solution was added to the residue,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (developing solvent: hexane/ethyl acetate=3/1v/v) to give 4.43 g ofN-tert-butoxycarbonyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenylethylamine.This compound was added to a 4N hydrogen chloride-dioxane solution (50ml), and the mixture was stirred at room temperature for 2 hours.Toluene was added to the reaction mixture, and the mixture wasconcentrated under reduced pressure. Ether was added to the residue forcrystallization to give the title compound (3.25 g, yield 47%).

PREPARATIVE EXAMPLE 7

O-Benzyl-L-phenylalaninol

To a solution of L-phenylalaninol (11.78 g) in THF (200 ml) wasgradually added 60% sodium hydride (3.43 g) in oil at room temperature.Twenty minutes later, the reaction mixture was refluxed under heatingfor 1 hour. Then, the mixture was allowed to cool, followed by gradualaddition of benzyl bromide (9.27 ml) under ice-cooling, and stirred atroom temperature for 16 hours. The reaction mixture was added tosaturated brine, and extracted with ether. The organic layer wasextracted with 10% hydrochloric acid. The aqueous layer was madealkaline with an aqueous sodium hydroxide solution, and extracted withether. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure togive the title compound (14.5 g, yield 77%).

EXAMPLE 1

N-[3,5-Dichloro-2-hydroxy-4-(4-methylaminobutoxy)benzoyl]-L-phenyl-alanine methyl ester hydrochloride

Step 1)3,5-Dichloro-2-hydroxy-4-(4-tert-butoxycarbonylmethyl-aminobutoxy)benzoicacid methyl ester (VI)

To a solution of 4-tert-butoxycarbonylmethylamino-1-butanol (3 g) andknown 3,5-dichloro-2,4-dihydroxybenzoic acid methyl ester (3.85 g) inTHF (80 ml) were added triphenylphosphine (4.26 g) and diisopropylazodicarboxylate (3.2 ml) under ice-cooling, and the mixture was stirredfor 16 hours. The reaction mixture was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (developing solvent: hexane/ethyl acetate=4/1 v/v) togive the title compound (5.2 g, yield 83%).

Step 4)3,4-Dichloro-2-hydroxy-4-(4-tert-butoxycarbonylmethylamino-butoxy)benzoicacid (VII)

The compound (3.46 g) obtained in the above Step 1) was dissolved in amixed solvent of methanol (12 ml)-THF (12 ml), and a 1M lithiumhydroxide solution (24 ml) was added to the mixture, which was followedby stirring with heating at 60° C. for 2 hours. After cooling with ice,the mixture was concentrated under reduced pressure. A 10% aqueouscitric acid solution (50 ml) was added to the residue to acidify same,and the mixture was extracted with ether (50 ml). The organic layer wasdried over anhydrous magnesium sulfate, and the solvent was distilledaway under reduced pressure to give the title compound (3.22 g, yield96%).

Step 5)N-[3,5-Dichloro-2-hydroxy-4-(4-tert-butoxycarbonylmethylamino-butoxy)benzoyl]-L-phenylalaninemethyl ester (1′)

To a solution of the compound (3 g) obtained in the above Step 4),L-phenylalanine methyl ester hydrochloride (1.59 g), WSC.HCl (1.41 g)and HOBT (1 g) in DMF (10 ml) was added dropwise triethylamine (1 ml) atroom temperature, and the mixture was stirred for 15 hours. Water (60ml) was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed successively with a 10%aqueous citric acid solution, water, a saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, and dried overanhydrous sodium sulfate. Then, the solvent was distilled away underreduced pressure. The residue was purified by silica gel columnchromatography (developing solvent: hexane/ethyl acetate=3/1 v/v to givethe title compound (2.72 g, yield 65%).

Step 6)N-[3,5-Dichloro-2-hydroxy-4-(4-methylaminobutoxy)benzoyl]-L-phenylalaninemethyl ester hydrochloride (I)

To a solution of the compound (5 g) obtained in the above Step 5) indioxane (10 ml) was added a 4N hydrogen chloride-dioxane solution (40ml), and the mixture was stirred at room temperature for 1.5 hours. Thereaction mixture was diluted with toluene, and concentrated underreduced pressure. Ether (50 ml) was added to the residue forcrystallization to give the title compound (4.2 g, yield 95%, see Table2).

EXAMPLE 1′

N-[3,5-Dichloro-2-hydroxy-4-(4-methylaminobutoxy)benzoyl]-L-phenyl-alanine methyl ester hydrochloride

Step 13) N-(3,5-Dichloro-2,4-dihydroxybenzoyl)-L-phenylalanine methylester (XVII)

To a solution of 3,4-dichloro-2,4-dihydroxybenzoic acid (17 g),L-phenylalanine methyl ester hydrochloride (19.8 g), WSC.HCl (17.6 g)and HOBT (12.4 g) in DMF (70 ml) was added dropwise triethylamine (12.8ml) at room temperature, and the mixture was stirred for 16 hours. Then,the mixture was post-treated in the same manner as in the above Example1, (Step 5) to give the title compound (18.32 g, yield 57%).

Step 14)N-[3,5-Dichloro-2-hydroxy-4-(4-tert-butoxycarbonylmethyl-aminobutoxy)benzoyl]-L-phenylalaninemethyl ester (I′)

To a solution of the compound (11.0 g) obtained in the above Step 13)and 4-tert-butoxycarbonylmethylamino-1-butanoyl (5.29 g) in THF (100 ml)were added triphenylphosphine (7.51 g) and diisopropyl azodicarboxylate(5.6 ml) under ice-cooling, and the mixture was stirred for 16 hours.The reaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (developingsolvent: hexane/ethyl acetate=3/1 v/v) to give the title compound (3.10g, yield 21%). Step 6)N-[3,5-Dichloro-2-hydroxy-4-(4-methylaminobutoxy)benzoyl]-L-phenylalaninemethyl ester hydrochloride (I)

To a solution of the compound (10 g) obtained in the above Step 14) indioxane (25 ml) was added dropwise a 4N hydrogen chloride-dioxanesolution (88 ml) at room temperature. After 1.5 hours, toluene wasadded. The solvent was distilled away under reduced pressure, and other(120 ml) was added to the residue for crystallization to give the titlecompound (8.4 g, yield 95%).

EXAMPLE 2

N-{3,5-Dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]-benzoyl}-L-phenylalanineethyl ester dihydrochloride

Step 1)3,5-Dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)-ethoxy]benzoic acidmethyl ester (VI)

To a solution of 2-(4-methylpiperazin-1-yl) ethanol (14.42 g) and3,5-dichloro-2,4-dihydroxybenzoic acid methyl ester (52.15 g) inchloroform (400 ml) were added triphenylphosphine (28.85 g) andazodicarboxylic acid diisopropyl (21.7 ml) at room temperature, and themixture was stirred for 16 hours, 1N Hydrochloric acid (300 ml) wasadded to the reaction mixture for extraction to give a crude product ofthe title compound. Step 4)3,5-Dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]-benzoic acid(VII)

To the extract of the crude product obtained in the above Step 1) wasadded a 4M aqueous sodium hydroxide solution (125 ml), and the mixturewas stirred under heating at 80° C. for 2 hours. Acetic acid (12.3 g)was further added to the mixture. The mixture was stirred underice-cooling, and applied to crystallization to give the title compound(27.880 g, yield 79%).

Step 5)N-{3,5-Dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]-benzoyl}-L-phenylalanineethyl ester dihydrochloride (I′=I)

To a solution of the compound (958 mg) obtained in the above Step 4),L-phenylalanine ethyl ester hydrochloride (923 mg) and HOBT (445 mg) inacetonitrile (15 ml) was added WSC.HCl (632 mg) at room temperature, andthe mixture was stirred for 25 hours. The reaction mixture wasconcentrated under reduced pressure, and chloroform was added to theresidue. The mixture was washed successively with a saturated aqueoussodium hydrogencarbonate solution, water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (developingsolvent: chloroform/methanol=10/1 v/v) to give a compound (1.386 g).Then, a 4N hydrogen chloride-ethyl acetate solution was added to asolution of the compound (1.003 g) in acetone (10 ml) forcrystallization to give the title compound (1.073 g, yield 93%, seeTable 2).

EXAMPLES 3-87

The compounds of Examples 3-87 were prepared in the same manner as inExample 1, Example 1′ and Example 2 from the corresponding compounds(see Tables 3-45).

EXAMPLE 88

N-[2-Hydroxy-4-(4-methylaminobutyl)benzoyl]-L- phenylalanine methylester hydrochloride

Step 3) 4-[4-(tert-Butoxycarbonylmethylamino)butyl]-2-hydroxybenzoicacid methyl ester (VI)

(1) 4-[4-(tert-Butoxycarbonylmethylamino)-1-butenyl]-2-hydroxybenzoicacid methyl ester

To a solution of[3-hydroxy-4-methoxycarbonyl)benzyl]triphenyl-phosphonium bromide (2.537g), obtained by a known method, in THF (25 ml) was added dropwise a 2Mlithium diisopropylamide-THF solution (5.5 ml) in a stream of argon at0° C., and the mixture was stirred for 30 minutes. Then, a solution of4-(tert-butoxycarbonylmethylamino) butylaldehyde (1.123 g), prepared bya known method, in THF (10 ml) was gradually added dropwise at 0° C.,and the mixture was stirred at room temperature for 4 hours. A saturatedaqueous ammonium chloride solution (1 ml) was gradually added, and themixture was concentrated under reduced pressure, which was followed byextraction with toluene. The extract was washed with a 10% aqueouscitric acid solution and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica tel column chromatography (developing solvent:hexane/ethyl acetate=4/1 v/v) to give the title compound (0.850 g, yield51%).

(2) 4-[4-(tert-Butoxycarbonylmethylamino)butyl]-2-hydroxybenzoic acidmethyl ester

A solution of the compound (0.845 g) obtained in (1) above in methanol(20 ml) was vigorously stirred in the presence of 10% palladium-carbon(0.106 g) in a stream of hydrogen. After filtering through Celite, themixture was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (developing solvent:hexane/ethyl acetate=4/1 v/v) to give the title compound (0.810 g, yield95%).

Step 4) 4-[5-(tert-Butoxycarbonylmethylamino)butyl]-2-hydroxybenozicacid (VII)

The compound (0.806 g) obtained in the above Step 3) was subjected tothe same reaction as the above Example 1, Step 4) to give the titlecompound (0.760 g, yield 98%). Step 5)N-[2-Hydroxy-4-(4-tert-butoxycarbonylmethylaminobutyl)benzoyl]-L-phenylalaninemethyl ester (I′)

The compound (0.753 g) obtained in the above Step 4) and L-phenylalaninemethyl ester hydrochloride (0.552 g) was subjected to the same reactionas in the above Example 1, Step 5) to give the title compound (0.714 g,yield 63%). Step 6)N-[2-Hydroxy-4-(4-methylaminobutyl)benzoyl]-L-phenylalanine methyl esterhydrochloride (I)

The compound (0.128 g) obtained in the above Step 5) was subjected tothe same reaction as in the above Example 1, Step 6) to give the titlecompound (0.87 g, yield 78%, see Table 46).

EXAMPLES 89, 90

The compounds of Examples 89 and 90 were prepared in the same manner asin Example 88 from the corresponding compounds (see Tables 46-47).

EXAMPLE 91

N-[3,5-Dichloro-2-hydroxy-4-(5-methylaminopentyl)benzoyl]-L-phenyl-alanine methyl ester hydrochloride

Step 11)4-[5-(tert-Butoxycarbonylmethylamino)pentyl]-3,5-dichloro-2-hydroxybenzoicacid methyl ester (VI)

To a solution of 4-[5-(tert-butoxycarbonylmethylamino)pentyl]-2-hydroxybenozic acid methyl ester (3.95 g), obtained in thesame manner as in the above Example 88, Step 3), in acetonitrile (35 ml)was added sulfuryl chloride (9 ml) at room temperature, and the mixturewas refluxed under heating at 60° C. for 1 hour. Toluene was added tothe reaction mixture and the mixture was concentrated under reducedpressure. Dichloromethane (85 ml) was added to the residue. Then,triethylamine (7.85 ml) and di-tert-butyl dicarbonate (4.9 g) wereadded, and the mixture was stirred at room temperature for 1 hour. Water(50 ml) was added to the reaction mixture for washing, and the mixturewas dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(developing solvent:hexane/ethyl acetate=4/1 v/v) to give the titlecompound (2.319 g, yield 50%).

Step 4)4-[5-(tert-Butoxycarbonylmethylamino)pentyl]-3,5-dichloro-2-hydroxybenzoicacid (VII)

The compound (2.319 g) obtained in the above Step 11) was subjected tothe same reaction as in the above Example 1, Step 4) to give the titlecompound (1.994 g, yield 89%). Step 5)N-[4-(5-tert-Butoxycarbonylmethylaminopentyl)-3,5-dichloro-2-hydroxybenzoyl]-L-phenylalaninemethyl ester (I′)

The compound (2.874 g) obtained in the above Step 4) and L-phenylalaninemethyl ester hydrochloride (1.522 g) was subjected to the same reactionas in the above Example 1, Step 5) to give the title compound (3.441 g,yield 86%). Step 6)N-[3,5-Dichloro-2-hydroxy-4-(5-methylaminopentyl)benzoyl]-L-phenylalaninemethyl ester hydrochloride (I)

The compound 3.426 g) obtained in the above Step 5) was subjected to thesame reaction as in the above Example 1, Step 6) to give the titlecompound (2.525 g, yield 83%, see Table 48).

EXAMPLES 92-104

The compounds of Examples 92-104 were prepared in the same manner as inExample 91 from the corresponding compounds (see Tables 48-54).

EXAMPLE 105

N-[2-Benzoyloxy-3,5-dichloro-4-(4-methylaminobutoxy)benzoyl]-L-phenylalaninemethyl ester hydrochloride

Step 12)N-[2-Benzoyloxy-3,5-dichloro-4-(4-tert-butoxycarbonylmethyl-aminobutoxy)benzoyl]-L-phenylalaninemethyl ester (I′)

To a solution of the compound (212 mg), obtained in the above Example 1,Step 5), in dichloromethane (3 ml) were added pyridine (60 μl) andbenzoyl chloride (80 μl) at room temperature, and the mixture wasstirred for 30 minutes. Water (5 ml) was added to the reaction mixtureand the mixture was extracted with ethyl acetate. The organic layer waswashed successively with a 10% aqueous citric acid solution, a saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine,and dried over anhydrous magnesium sulfate. Then, the solvent wasdistilled away under reduced pressure. The residue was purified bysilica gel column chromatography (developing solvent: hexane/ethylacetate-3/1 v/v) to give the title compound (224 mg, yield 95%).

Step 6)N-[2-Benzoyloxy-3,5-dichloro-4-(4-methylaminobutoxy)benzoyl]-L-phenylalaninemethyl ester hydrochloride (I)

The compound (224 mg) obtained in the above step 12) was subjected tothe same reaction as in the above Example 1, Step 6) to give the titlecompound (159 mg, yield 83%, see Table 55).

EXAMPLES 106-125

The compounds of Examples 106-125 were prepared in the same manner as inExample 105 from the corresponding compounds (see Tables 55-65).

EXAMPLE 126

N-[3,5-Dichloro-2-hydroxy-4-(4-methylaminobutoxy)benzoyl]-L-phenylalanine hydrochloride

Step 6)N-[3,5-Dichloro-2-hydroxy-4-(4-methylaminobutoxy)benzoyl]-L-phenylalaninehydrochloride (I)

To a solution ofN-[3,5-dichloro-2-hydroxy-4-(4-tert-butoxy-carbonylmethylaminobutoxy)benzoyl]-L-phenylalaninetert-butyl ester (490 mg), obtained in the same manner as in the aboveExample 1, Step 5), in dichloromethane (8 ml) was added trifluoroaceticacid (4 ml) at room temperature, and the mixture was stirred for 14hours. Toluene was added to the reaction mixture and the mixture wasconcentrated under reduced pressure. A 1M hydrogen chloride-ethersolution (5 ml) was added to the residue for crystallization to give thetitle compound (250 mg, yield 67%, see Table 66).

EXAMPLES 127-135

The compounds of Examples 127-135 were prepared in the same manner as inExample 126 from the corresponding compounds (see Tables 66-70).

EXAMPLE 136

N-[3,5-Dichloro-2-hydroxy-4-(4-methylaminobutylamino)benzoyl]-L-phenylalaninemethyl ester dihydrochloride

Step 16)N-[2-Hydroxy-4-(4-tert-butoxycarbonylmethylaminobutylamino)-benzoyl]-L-phenylalaninemethyl ester (I′)

A solution of N-[(4-amino-2-hydroxy)benzoyl]-L-phenylalanine methylester (1.11 g) obtained in the same manner as in the above Example 1′,Step 13) and 4-tert-butoxycarbonylmethylamino)-1-butylaldehyde (711 mg)in methanol (20 ml) was stirred at room temperature in a stream of argonfor 4 hours. 10% Palladium-carbon (200 mg) was added to the reactionmixture, and the mixture was subjected to catalytic hydrogenation usinghydrogen gas under atmospheric pressure. Four hours later, the reactionmixture was filtered, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(developing solvent: hexane/ethyl acetate=3/2 v/v) to give the titlecompound (900 mg, yield 51%).

Step 11)N-[3,5-Dichloro-2-hydroxy-4-(4-tert-butoxycarbonylmethyl-aminobutylamino)benzoyl]-L-phenylalaninemethyl ester (I′)

To a solution of the compound (900 mg) obtained in the above Step 16) indichloromethane (20 ml) was added dropwise tert-butyl hypochlorite (0.46ml) under ice-cooling, and the mixture was stirred under ice-cooling for50 minutes. The reaction mixture was washed with water and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasdistilled away under reduced pressure, and the residue was purified bysilica gel column chromatography (developing solvent: hexane/ethylacetate-3/1 v/v) to give the title compound (830 mg, yield 82%).

Step 6)N-[3,5-Dichloro-2-hydroxy-4-(4-methylaminobutylamino)benzoyl]-L-phenylalaninemethyl ester dihydrochloride (I)

To a solution of the compound (280 mg) obtained in the above Step 11) inchloroform (5 ml) was added trifluoroacetic acid (2.5 ml) at roomtemperature, and the mixture was stirred for 20 minutes. Toluene wasadded to the reaction mixture and the mixture was concentrated underreduced pressure. A 1M hydrogen chloride-ether solution was added to theresidue for crystallization to give the title compound (218 mg, yield82%, see Table 71).

EXAMPLE 137

The compound of Example 137 was prepared in the same manner as inExample 136 from the corresponding compound (see Table 7).

EXAMPLE 138

N-[3,5-Dichloro-2-hydroxy-4-(4-aminobutoxy)benzoyl]-L-phenyl-alanylaminobenzenehydrochloride

3,5-Dichloro-2-hydroxy-4-(4-tert-butoxycarbonylaminobutoxy)-benzoic acid(347 mg) obtained in the same manner as in the above Example 1, Step 4)and L-phenylalanylaminobenzene hydrochloride (268 mg) were subjected tothe same reaction as in the above Example 1, Step 5) and Step 6) to givethe title compound (284 mg, yield 58%, see Table 72).

EXAMPLES 139-142

The compounds of Examples 139-142 were prepared in the same manner as inExample 138 from the corresponding compounds (see Tables 72-74).

EXAMPLE 143

N-[3,5-Dichloro-2-hydroxy-4-(4-methylaminobutoxy)benzoyl]-L-phenylalanylhydroxyamide

Step 5)N-[3,5-Dichloro-2-hydroxy-4-(4-benzyloxycarbonylmethylamino-butoxy)benzoyl]-L-phenylalanyl-0-benzylhydroxylamide(I′)

3,5-Dichloro-2-hydroxy-4-(4-benzyloxycarbonylaminobutoxy)benzoic acid(237 mg) obtained in the same manner as in the above Example 1, Step 4)and L-phenylalanyl-O-benzylhydroxyamide hydrochloride (203 mg) weresubjected to the same reaction as in the above Example 1, Step 5) togive the title compound (325 mg, yield 59%).

Step 6)N-[3,5-Dichloro-2-hydroxy-4-(4-methylaminobutoxy)benzoyl]-L-phenylalanylhydroxyamide(I)

To a solution of the compound 210 mg) obtained in the above Step 5) inmethanol (5 ml) was added palladium hydroxide (42 mg), and the mixturewas subjected to catalytic hydrogenation using hydrogen gas underatmospheric pressure. Twelve hours later, the reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure.Methanol-ether was added to the residue for crystallization to give thetitle compound (188 mg, yield 62%, see Table 74).

EXAMPLE 144

N-[4-(4-Aminobutoxy)-3,5-dichloro-2-hydroxybenzoyl]-1-(3-methyl-1,2,4-oxadizaol-5-yl)-2-phenylethylaminehydrochloride

3,5-Dichloro-2-hydroxy-4-(4-tert-butoxycarbonylaminobutoxy)-benzoic acid(394 mg) obtained in the same manner as in the above Example 1, Step 4)and 1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenylethylamine hydrochloride(240 mg) were subjected to the same reaction as in the above Example 1,Step 5) and Step 6) to give the title compound (229 mg, yield 58%, seeTable 75).

EXAMPLE 145

N-[4-(4-Aminobutoxy)-3,5-dichloro-2-hydroxybenzoyl]-L-phenyl-alaninolhydrochloride

3,5-Dichloro-2-hydroxy-4-(4-tert-butoxycarbonylaminobutoxy)-benzoic acid(394 mg) obtained in the same manner as in the above Example 1, Step 4)and O-benzyl-L-phenylalaninol (242 mg) were subjected to the samereaction as in the above Example 1, Step 5), Example 99, Step 6) andExample 1, Step 6) to give the title compound (190 mg, yield 42%, seeTable 75).

EXAMPLE 146

(2S)-3-Phenyl-2-[5-(4-aminobutoxy)-3-hydroxy-2-naphthoylamino]-propionicacid methyl ester hydrochloride

Step 13) (2S)-3-Phenyl-2-(3,5-dihydroxy-2-naphthoylamino)propionic acidmethyl ester (XVII)

A solution of 3,5-dihydroxy-2-naphthoic acid (4.08 g), L-phenylalaninemethyl ester hydrochloride (4.74 g), WSC.HCl (4.22 g), HOBT (2.97 g) andN-methylmorpholine (2.41 ml) in DMF (200 ml) was stirred at roomtemperature for 16 hours. Water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer waswashed successively with a 10% aqueous citric acid solution, water, asaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (developing solvent: hexane/ethyl acetate-1/1 v/v) togive the title compound (4.42 g, yield 61%).

Step 14)(2S)-3-Phenyl-2-[5-(4-tert-butoxycarbonylaminobutoxy)-3-hydroxy-2-naphthoylamino]propionicacid methyl ester (I′)

To a solution of the compound (1.83 g) obtained in the above Step 13),triphenylphosphine (1.31 g) and 4-tert-butoxycarbonylaminobutyl alcohol(473 mg) in THF (25 ml) was added dropwise diisopropyl azodicarboxylate(0.98 ml) at room temperature. After stirring at room temperature for 16hours, the reaction mixture was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography (developingsolvent: hexane/ethyl acetate=2.1 v/v) to give the title compound (375mg, yield 30%).

Step 6)(2S)-3-Phenyl-2-[5-(4-aminobutoxy)-3-hydroxy-2-naphthoylamino]-propionicacid methyl ester hydrochloride (I)

To a solution of the compounded (375 mg) obtained in the above Step 14)in THF (5 ml) was added a 4N hydrogen chloride-dioxane solution (5 ml),and the mixture was stirred at room temperature for 3 hours. The mixturewas concentrated under reduced pressure. Ether was added to the residuefor crystallization to give-the title compound (187 mg, yield 57%, seeTable 76).

EXAMPLE 147

N-[4-[4-(4-Methylaminobutoxy)phenyl]benzoyl]-L-phenylalanine ethyl esterhydrochloride

Step 13) 4-(4-Hydroxyphenyl)benzoyl-L-phenylalanine ethyl ester (XVII)

To a solution of 4-(4-hydroxyphenyl)benzoic acid (3.0 g) andL-phenylalanine ethyl ester hydrochloride (3.38 g) in DMF (30 ml) wereadded WSC.HCl (2.7 g), HOBT (1.89 g) and triethylamine (2 ml), and themixture was stirred at room temperature for 14 hours. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was washed successively with a 10 % aqueous citricacid solution, water, a saturated aqueous sodium hydrogen-carbonatesolution, water and saturated brine, dried over magnesium sodiumsulfate, and concentrated under reduced pressure to give a crude productof the title compound.

Step 15)N-[4-[4-(4-tert-Butoxycarbonylmethylaminobutoxy)phenyl]-benzoyl]-L-phenylalanineethyl ester (I′)

To a solution of the crude product obtained in the above Step 13) in DMF(30 ml) were added 4-(tert-butoxycarbonylmethylamino)butyl bromide (4.46g) and potassium carbonate (4.65 g), and the mixture was stirred at roomtemperature for 14 hours. Ethyl acetate was added to the reactionmixture. The mixture was washed successively with water, a 10% aqueouscitric acid solution and saturated brine, and dried over anhydroussodium sulfate. The organic layer was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (developing solvent: hexane/ethyl acetate=3/1 v/v) togive the title compound (967 mg, yield 10%).

Step 6) N-[4-[4-(4-Methylaminobutoxy)phenyl]benzoyl]-L-phenylalanineethyl ester hydrochloride (I)

To a solution of the compound (140 mg) obtained in the above Step 14) inTHF (2 ml) was added a 4N hydrogen chloride-dioxane solution (2 ml). Themixture was stirred at room temperature for 4 hours, and concentratedunder reduced pressure. Ether was added to the residue forcrystallization to give the title compound (71 mg, yield 58%, see Table76).

EXAMPLE 148

(2S)-3-Phenyl-2-[4-[5-(4-methylaminobutyl)-1,2,4-oxadizol-3-yl]-2-hydroxybenzoylamino]propionicacid ethyl ester hydrochloride

Step 9) Methyl 2-hydroxybenzoate-4-carboxamideO-(4-tert-butoxycarbonyl-methylaminovaleryl) oxime (XV)

A solution of 4-tert-butoxycarbonylmethylaminovaleric acid (255 mg),methyl 2-hydroxybenzoate-4-carboxamide oxime (210 mg), WSC.HCl (211 mg)and 4-dimethylaminopyridine (DMAP, 135 mg) in dichloromethane (5 ml) wasstirred at room temperature for 16 hours. Water was added to thereaction mixture and the mixture was extracted with ethyl acetate. Theorganic layer was washed successively with a 10% aqueous citric acidsolution water, a saturated aqueous sodium hydrogencarbonate solution,water and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (developing solvent: hexane/ethyl acetate=1/1v/v) to give the title compound (229 mg, yield 54%).

Step 10) 2Hydroxy-4-[5-(4-tert-butoxycarbonylmethylaminobutyl)-1,2,4-oxadiazol-3-yl]benzoicacid methyl ester (VI′)

A solution of the compound (224 mg) obtained in the above Step 9) intoluene (20 ml) was refluxed under heating for 16 hours. The reactionmixture was allowed to cool, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (developingsolvent: hexane/ethyl acetate=3/1 v/v) to give the title compound (148mg, yield 69%).

Step 4)2-Hydroxy-4-[5-(4-tert-butoxycarbonylmethylaminobutyl)-1,2,4-oxadiazol-3-yl]benzoicacid (VII)

To a solution of the compound (146 mg) obtained in the above Step 10) inethanol (10 ml) was added a 1M lithium hydroxide solution (5 ml), andthe mixture was refluxed under heating for 2 hours. The reaction mixturewas concentrated under reduced pressure, and a 10% aqueous citric acidsolution was added to the residue, which was followed by extraction withethyl acetate. The organic layer was washed with water, and dried overanhydrous sodium sulfate. The organic layer was concentrated underreduced pressure to give the title compound (140 mg, yield 99%).

Step 5)(2S)-3-Phenyl-2-[4-[5-(4-tert-butoxycarbonylmethylaminobutyl)-1,2,4-oxadiazol-3-yl]-2-hydroxybenzoylamino]propionicacid ethyl ester (I′)

A solution of the compound (140 mg) obtained in the above Step 4)L-phenylalanine ethyl ester hydrochloride (92 mg), WSC.HCl (77 mg), HOBT(54 mg) and triethylamine (0.056 ml) in DMF (1.5 ml) was stirred at roomtemperature for 15 hours. Water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The organic layer waswashed successively with a 10% aqueous citric acid solution water, asaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (developing solvent: hexane/ethyl acetate=2/1 v/v) togive the title compound (174 mg, yield 85%).

Step 6)(2S)-3-Phenyl-2-[4-[5-(4-methylaminobutyl)-1,2,4-oxadizol-3-yl]-2-hydroxybenzoylamino]propionicacid ethyl ester hydrochloride (I)

To a solution of the compound (172 mg) obtained in the above Step 5) inTHF (2 ml) was added a 4N hydrogen chloride-dioxane solution (2 ml), andthe mixture was stirred at room temperature for 3 hours. The reactionmixture was concentrated under reduced pressure, and ether was added tothe residue for crystallization to give the title compound (1.33 mg,yield 87%, see Table 77).

EXAMPLES 149-151

The compounds of Examples 149-151 were prepared in the same manner as inExample 148 from the corresponding compounds (see Tables 77-78).

EXAMPLE 152

(2S)-2-[2-(3-Methylaminopropylsulfanyl)benzoxazole-5-carbonyl-amino]-3-phenylpropionicacid ethyl ester hydrochloride

Step 2)1-(3-tert-Butoxycarbonylmethylaminopropylsulfanyl)-5-ethoxy-carbonylbenzoxazole(VI)

To a solution of 5-ethoxycarbonyl-2-mercaptobenzoxazole (670 mg) in DMFwas added 60% sodium hydride (126 mg) in oil under ice-cooling, and themixture was stirred for 30 minutes. A solution of3-tert-butoxycarbonylmethylaminopropyl chloride (623 mg) in DMF wasadded to the reaction mixture, and the mixture was stirred with heatingat 60° C. for 18 hours. Ethyl acetate was added to the reaction mixture,and the organic layer was washed with water and dried over anhydroussodium sulfate. The organic layer was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (developing solvent: hexane/ethyl acetate=4/1 v/v) togive the title compound (594 mg, yield 50%).

Step 4)2-(3-tert-Butoxycarbonylmethylaminopropylsulfanyl)-5-carboxy-benzoxazole(VII)

To a mixed solution of the compound (562 mg) obtained in the above Step2) in ethanol (2 ml)-THF (2 ml) was added a 1M lithium hydroxidesolution, and the mixture was stirred with heating at 60° C. for 1 hour.The reaction mixture was concentrated under reduced pressure, and ethylacetate and a 10% aqueous citric acid solution were added. The organiclayer was dried over anhydrous sodium sulfate, and concentrated underreduced pressure to give the title compound (465 mg, yield 98%).

Step 5)(2S)-2-[2-(3-tert-Butoxycarbonylmethylaminopropylsulfanyl)-benzoxazole-5-carbonylamino]-3-phenylpropionicacid ethyl ester (I′)

A solution of the compound (465 mg) obtained in the above Step 4),L-phenylalanine ethyl ester hydrochloride (302 mg), WSC.HCl (250 mg),HOBT (176 mg) and triethylamine (0.18 ml) in DMF was stirred at roomtemperature for 14 hours. Water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. The organic layer waswashed successively with a 10% aqueous citric acid solution, water, asaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (developing solvent: hexane/ethyl acetate=4/1 v/v) togive the title compound (240 mg, yield 40%).

Step 6) (2S)-2-[2-(3-Methylaminopropylsulfanyl)benzoxazole-5-carbonyl-amino]-3-phenylpropionic acid ethyl esterhydrochloride (I)

To a solution of the compound (231 mg) obtained in the above Step 5) inTHF (5 ml) was added a 4N hydrogen chloride-dioxane solution (5 ml), andthe mixture was stirred at room temperature for 4 hours. The reactionmixture was concentrated under reduced pressure, and ether was added forcrystallization to give the title compound (136 mg, yield 67%, see Table79).

EXAMPLES 153-154

The compounds of Examples 153-154 were prepared in the same manner as inExample 152 from the corresponding compounds (see Tables 79-80).

EXAMPLE 155

N-[3,5-Dichloro-2-hydroxy-4-(3-piperazinylpropionyloxy)benzoyl]-L-phenylalanineethyl ester dihydrochloride

Step 18)N-[3,5-Dichloro-2-hydroxy-4-[3-(4-tert-butoxycarbonyl-piperazinyl)propionyloxy]benxoyl]-L-phenylalanineethyl ester (I′)

To a solution of N-(3,5-dichloro-2,4-dihydroxybenzoyl)-L-phenyl-alanineethyl ester (398 mg) obtained in the same manner as in the above ExampleI′, Step 13) 3-(4-tert-butoxycarbonylpiperazinyl)propionic acid (258 mg)and 4-dimethylaminopyridine (147 mg) in DMF (4 ml) was added WSC.HCl(230 mg) under ice-cooling, and the mixture was stirred at roomtemperature for 2 hours. Ethyl acetate (40 ml) was added to the reactionmixture, and the mixture was washed successively with water, a saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine.The reaction mixture was dried over anhydrous sodium sulfate, and thesolvent was distilled away under reduced pressure. The residue waspurified by silica gel column chromatography (developing solvent: ethylacetate/hexane=1/1 v/v) to give the title compound (258 mg, yield 40%)

Step 6)N-[3,5-Dichloro-2-hydroxy-4-(3-piperazinylpropionyloxy)benzoyl]-L-phenylalanineethyl ester dihydrochloride (I)

To a solution of the compound (258 mg) obtained in the above Step 18) indichloromethane (2 ml) was added trifluoracetic acid (2 ml), and themixture was stirred at room temperature for 10 minutes. The solvent wasdistilled away under reduced pressure, and 1M hydrogen chloride-ether (3ml) was added for crystallization to give the title compound (173 mg,yield 70%, see Table 81).

EXAMPLES 156-158

The compounds of Examples 156-158 were prepared in the same manner as inExample 155 from the corresponding compounds (see Tables 81-82).

The structures and physical properties for the compounds of the aboveExamples are shown in the following Tables 2-82.

In the Tables, Me, Et, Ph, Bn and Ac mean methyl, ethyl, phenyl, benzyland acetyl, respectively.

TABLE 2 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 1

DMSO-d₆ 1.82(4H, bs) 2.56(3H, t, J=5.4Hz) 2.96(2H, bs) 3.04-3.28(2H, m)3.66(3H, s) 4.05(2H, bs) 4.72-4.82(1H, m) 8.17(1H, s) 8.48(2H, bd)9.44(1H, bs) 13.35(1H, s) KBr 3422 2953 1742 1637 1458 1219 469 (freebase, # MH⁺) C₂₂H₂₆Cl₂N₂O₅.HCl Calculated C, 52.24 H, 5.38 N, 5.53 FoundC, 52.05 H, 5.37 N, 5.51 2

DMSO-d₆ 1.14(3H, t, J=6.0Hz) 2.81(3H, s) 3.0-3.60(10H, m) 4.11(2H, q,J=6.0Hz) 4.34(2H, brs) 4.68-4.78(1H, m) 7.19-7.29(5H, m) 8.22(1H, s)9.46(1H, d, J=7.0Hz) 13.40(1H, brs) KBr 3406 2957 2372 1736 1642 1458524 (free base, # MH⁺) C₂₅H₃₁Cl₂N₂O₅.2HCl Calculated C, 50.27 H, 5.57 N,7.03 Found C, 50.19 H, 5.74 N, 6.93 

TABLE 3 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 3

DMSO-d₆ 1.86-2.04(2H, m) 2.82-2.92(2H, m) 3.02-3.18(2H, m) 3.64(3H, s)4.06-4.37(2H, m) 4.72-4.84(1H, m) 6.42-6.52(2H, m) 7.16-7.34(5H, m)7.65(1H, d, J=8.5Hz) 7.96(3H, brs) 8.21(1H, d, J=7.4Hz) 10.24(1H, s) KBr3383 1739 1632 1607 # 1534 1498 372 (free base, MH⁺) 4

DMSO-d₆ 1.46-1.73(4H, m) 2.63-2.86(2H, m) 3.00-3.18(2H, m) 3.64(3H, s)3.92-4.11(2H, m) 4.78-4.89(1H, m) 6.43-6.53(2H, m) 7.10-7.34(5H, m)7.75(1H, d, J=8.5Hz) 7.82-8.04(3H, brs) 8.22(1H, d, J=7.0Hz) 10.24(1H,s) KBr 3378 1630 1604 # 1534 1498 386 (free base, MH⁺) 

TABLE 4 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 5

DMSO-d₆ 1.18-1.42(2H, m) 1.43-1.54(4H, m) 2.62-2.78(2H, m) 3.02-3.21(2H,m) 3.67(3H, s) 3.91-4.08(2H, m) 4.82-4.94(1H, m) 6.42-6.52(2H, m)7.20-7.36(3H, m) 7.78(1H, d, J=8.4Hz) 7.80-7.94(3H, brs) 8.24(1H, d,J=7.3Hz) 10.25(1H, s) KBr 1630 1604 # 1534 1498 1201 400 (free base,MH⁺) 6

DMSO-d₆ 1.14-1.34(4H, m) 1.40-1.61(4H, m) 2.66-2.80(2H, m) 3.01-3.16(2H,m) 3.92-4.04(2H, m) 4.80-4.90(1H, m) 6.44(1H, d, J=2.2Hz) 6.48(1H, dd,J=8.4, 2.2Hz) 7.10-7.32(5H, m) 7.77(1H, d, J=8.4Hz) 7.85(3H, brs)8.24(1H, d, J=7.4Hz) 10.22(1H, brs) KBr 3378 # 1630 1605 1534 1498 1181414 (free base, MH⁺) 

TABLE 5 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 7

DMSO-d₆ 1.71-1.88(4H, m) 2.48-2.57(3H, m) 2.90-3.01(2H, m) 3.10-3.25(2H,m) 3.66(3H, s) 4.16(2H, t, J=6Hz) 4.69-4.76(1H, m) 6.78(1H, d, J=9Hz)7.16-7.32(5H, m) 7.94(1H, d, J=9Hz) 8.70(2H, brs) 9.26(1H, d, J=9Hz)13.35(1H, s) Neat 2954 1728 # 1642 1589 1548 1497 435 (free base, MH⁺) 8

DMSO-d₆ 1.14(3H, t, J=6Hz) 1.72-1.88(4H, m) 2.49-2.55(3H, m)2.90-3.02(2H, m) 3.10-3.24(2H, m) 4.11(2H, q, J=6Hz) 4.17(2H, t, J=6Hz)4.65-4.73(1H, m) 6.79(1H, d, J=9Hz) 7.17-7.32(5H, m) 7.95(1H, d, J=9Hz)8.09(2H, brs) 9.23(1H, d, J=6Hz) 13.37(1H, s) #Neat 2958 1773 1641 15881547 1497 449 (free base, MH⁺) 

TABLE 6 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 9

DMSO-d₆ 1.70-1.86(4H, m) 2.53(3H, s) 2.92-3.02(2H, m) 3.05-3.23(2H, m)3.65(3H, s) 4.07-4.17(2H, m) 4.68-4.78(1H, m) 6.65(1H, s) 8.60(2H, brs)8.99(1H, d, J=7.0Hz) 12.49(1H, brs) 435 (free base, MH⁺) 10

DMSO-d₆ 1.78-1.84(4H, m) 2.09(3H, s) 2.53(3H, bs) 2.95(2H, bs)3.08-3.24(2H, m) 3.66(3H, s) 3.88-3.94(2H, m) 4.68-4.82(1H, m)7.18-7.32(5H, m) 8.03(1H, s) 8.78(2H, bs) 9.29(1H, d, J=7.7Hz) 12.92(1H,s) KBr 2950 2783 1745 1637 1544 # 1465 1369 1264 449 (free base, MH⁺) 

TABLE 7 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 11

DMSO-d₆ 2.65-2.69(3H, m) 3.09-3.22(2H, m) 3.36-3.42(2H, m) 3.64-3.67(3H,m) 3.66(3H, s) 4.28(2H, t, J=6.0Hz) 4.74-4.81(1H, m) 7.19-7.29(5H, m)8.23(1H, s) 8.95-9.03(2H, m) 9.53(1H, d, J=5.0Hz) 13.38(1H, s) KBr 34222952 2730 1744 # 1942 1585 1458 1353 1221 441 free base, MH⁺)C₂₀H₂₂Cl₂N₂O₅.HCl Calculated C, 50.28 H, 4.85 N, 5.86 Found C, 50.19 H,4.69 N, 5.74 12

DMSO-d₆ 1.65-1.95(4H, m) 2.77-2.94(2H, m) 3.15(1H, dd, J=14.0, 9.Hz)3.24(1H, dd, J=14.0, 6.0Hz) 3.66(3H, s) 4.00-4.14(2H, m) 4.65-4.90(1H,m) 7.15-7.40(5H, m) 7.87(3H, brs) 8.19(1H, s) 9.45(1H, d, J=6.0Hz)13.35(1H, s) KBr 2953 1641 1585 1542 # 1457 1355 1221 455 free base,MH⁺) C₂₁H₂₄Cl₂N₂O₅.HCl Calculated C, 53.29 H, 5.12 N, 5.70 Found C,50.78 H, 5.17 N, 5.58 

TABLE 8 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 13

DMSO-d₆ 1.63-1.95(4H, m) 2.55((3H, s) 2.92-3.07(4H, m) 3.57(3H, s)3.88(2H, t, J=6.0Hz) 4.65-4.71(1H, m) 7.18-7.30(6H, m) 7.50(1H, s)8.41(1H, brds) 12.25-12.27(1H, m) KBr 3423 2951 1743 1618 1571 1541 14341205 1065 #469 (MH⁺) 14

DMSO-d₆ 1.84(4H, s) 2.54(3H, s) 2.90-3.25(4H, m) 3.58(3H, s) 3.68(3H, s)4.02(2H, m) 4.76(1H, m) 7.20-7.32(5H, m) 7.41(1h, m) 8.75(1H, d, J=9Hz)483 (free base, MH⁺) 

TABLE 9 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 15

DMSO-d₆ 1.79-1.89(4H, m) 2.55(2H, t, J=6.0Hz) 2.85-3.00(2H, m) 3.06(3H,dd, J=15.5, 8.4Hz) 3.57(3H, s) 3.65(3H, s) 4.01-4.11(1H, m)4.50-4.53(2H, m) 4.59-4.71(1H, m) 6.66(2H, d, J=9.0Hz) 7.06(2H, d,J=6.0Hz) 8.20(1H, brs) 8.65(2H, brs) 9.26(1H, s) # 9.40(1H, d, J=4.0Hz)13.37(1H, s) KBr 1640 1586 1515 1458 1354 1221 485 (free base, MH⁺)C₂₂H₂₆Cl₂N₂O₆.HCl Calculated C, 50.64 H, 5.22 N, 5.37 Found C, 49.62 H,5.29 N, 5.46 

TABLE 10 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 16

DMSO-d₆ 1.20(3H, t, J=6.0Hz) 1.82-1.88(4H, m) 2.92-2.95(4H, m)3.09-3.33(2H, m) 3.66(3H, s) 4.03-4.07(2H, m) 4.71-4.79(1H, m)7.19-7.29(5H, m) 8.20(1H, s) 8.58-8.76(2H, m) 9.48(1H, d, J=6.0Hz)13.35(1H, s) KBr 2954 1747 1641 # 1584 1542 1458 1354 1219 483 (freebase, MH⁺) C₂₅H₂₈Cl₂N₂O₅.HCl Calculated C, 53.14 H, 5.62 N, 5.39 FoundC, 52.54 H, 5.50 N, 5.40 17

CDCl₃ 1.80-1.91(2H, m) 1.95-2.07(2H, m) 2.59(6H, s) 2.96-3.13(2H, m)3.18-3.32(2H, m) 3.73(3H, s) 3.96-4.07(2H, m) 5.15(1H, t, J=6Hz)7.10-7.30(5H, m) 7.85(1H, s) 9.97(1H, brs) Neat 2952 2360 1743 1633 1437483 # (MH⁺) 

TABLE 11 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 18

CDCl₃ 1.90-2.01(2H, m) 2.13-2.25(2H, m) 2.83(6H, s) 3.13-3.30(4H, m)3.81(3H, s) 4.09(2H, t, J=6Hz) 5.02(1H, q, J=7Hz) 7.14-7.43(7H, m)7.48(1H, s) Neat 3241 2955 2671 1743 1640 1584 1461 483 # (free base,MH⁺) C₂₃H₂₈Cl₂N₂O₅.HCl Calculated C, 53.14 H, 5.62 N, 5.39 Found C,53.24 H, 5.63 N, 5.34 19

DMSO-d₆ 1.14(3H, t, J=6.0Hz) 1.70-1.95(4H, m) 2.80-2.95(2H, m)3.05-3.28(2H, m) 3.95-4.15(4H, m) 4.60-4.75(1H, m) 7.18-7.40(5H, m)7.91(3H, brs) 8.21(1H, s) 9.47(1H, d, J=6.0Hz) 13.36(1H, s) KBr 29611722 1706 1643 1544 # 1459 1354 1216 469 (free base, MH⁺)C₂₂H₂₆Cl₂N₂O₅.HCl Calculated C, 52.34 H, 5.19 N, 5.55 Found C, 51.62 H,5.41 N, 5.48 

TABLE 12 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 20

DMSO-d₆ 1.20(3H, t, J=7Hz) 1.81(4H, brs) 2.55-3.39(7H, m) 3.96(2H, brs)4.01-4.28(2, 3H, m) 5.15(0.7H, m) 6.94-7.39(5H, m) 7.9(3H, brs)10.14(1H, brs) KBr 3422 2959 1736 1627 1447 1406 1333 1182 483 (free #base, MH⁺) C₂₃H₂₆Cl₂N₂O₅.HCl Calculated C, 53.14 H, 5.62 N, 5.39 FoundC, 52.85 H, 5.69 N, 5.24 21

CDCl₃ 1.16(3H, t, J=8Hz) 1.50-1.75(4H, m) 2.38(3H, s) 2.90-3.05(2H, m)3.26(2H, dq, J=12Hz) 3.30-3.45(2H, m) 4.00-4.10(2H, m) 5.02-5.10(1H, m)7.10-7.15(2H, m) 7.20-7.30(3H, m) 8.00(1H, s) 10.76(1H, brs) 483 (MH⁺) 

TABLE 13 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 22

DMSO-d₆ 1.14(3H, t, J=6.0Hz) 1.77-1.91(4H, m) 2.54(3H, t, J=6.0Hz)2.89-3.00(2H, m) 3.13(1H, dd, J=9.0, 15.0Hz) 3.22(1H, dd, J=6.6, 15.0Hz)4.00-4.11(2H, m) 4.08(2H, q, J=6.0Hz) 4.68-4.79(1H, m) 7.18-7.32(5H, m)8.21(1H, s) 8.72 #(2H, brs) 9.48(1H, d, J=6.9Hz) 13.36(1H, s) KBr 17401584 1459 1352 1216 483 (free base, MH⁺) C₂₃H₂₈Cl₂N₂O₅.HCl Calculated C,53.14 H, 5.62 N, 5.39 Found C, 53.36 H, 5.71 N, 5.53 23

CDCl₃ 1.27(3H, t, J=7.5Hz) 1.82-2.04(4H, m) 2.55(6H, s) 2.95-3.11(2H, m)3.25(2H, d, J=4Hz) 3.93-4.04(2H, m) 4.12-4.22(2H, m) 5.11-5.18(1H, m)7.13-7.30(5H, m) 7.90(1H, s) 10.31(1H, brs) Neat 2956 1738 1634 15741538 1440 #497 (MH⁺) 

TABLE 14 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 24

DMSO-d₆ 1.13(3H, t, J=7.5Hz) 1.76-1.95(4H, m) 2.74(6H, s) 3.06-3.24(4H,m) 4.04-4.14(4H, m) 4.68-4.75(1H, m) 7.18-7.29(5H, m) 8.21(1H, s)9.54(1H, brs) Neat 2956 1738 1639 1583 1461 497 (free base, # MH⁺)C₂₂H₂₆Cl₂N₂O₅.HCl Calculated C, 53.99 H, 5.85 N, 5.25 Found C, 54.11 H,5.86 N, 5.27 25

DMSO-d₆ 1.13(3H, t, J=6.0Hz) 1.30-1.62(6H, m) 1.65-1.80(2H, m)2.80-2.88(2H, m) 3.03-3.27(2H, m) 3.98-4.15(4H, m) 4.60-4.78(1H, m)7.10-7.40(5H, m) 7.78(3H, brs) 8.19(1H, s) 9.44(1H, d, J=6.0Hz)13.35(1H, s) KBr 1641 1585 1458 1219 497 # (free base, MH⁺)C₂₄H₃₀Cl₂N₂O₅.HCl Calculated C, 53.99 H, 5.85 N, 5.25 Found C, 52.75 H,5.59 N, 4.72 

TABLE 15 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 26

DMSO-d₆ 1.13(3H, t, J=7.1Hz) 1.33-1.36(4H, m) 1.47-1.58(4H, m)1.73-1.83(2H, m) 2.72-2.82(2H, m) 3.08-3.26(2H, m) 4.03(2H, t, J=6.4Hz)4.11(2H, q, J=7.1Hz) 4.66-4.73(1H, m) 7.18-7.29(5H, m) 7.73-7.84(3H, m)8.19(H, s) 9.45(1H, d, J=7.1Hz) 13.36(1H, s) KBr # 3420 2936 1719 16411585 1543 1458 1352 1219 511 (free base, MH⁺) C₂₅H₃₂Cl₂N₂O₅.HClCalculated C, 54.80 H, 6.07 N, 5.11 Found C, 53.81 H, 6.10 N, 4.96 27

DMSO-d₆ 1.08-1.10(3H, d, J=6.0Hz) 1.17-1.19(3H, d, J=6.0Hz) 1.82(4H,brs) 2.88(2H, brs) 3.10-3.30(2H, m) 4.04(2H, brs) 4.60-4.90(2H, m)7.21-7.30(5H, m) 7.89(3H, brs) 8.19(1H, s) 9.50(1H, brs) 13.38(1H, brs)KBr 3420 2981 1717 1641 1585 # 1458 483 (free base, MH⁺)C₂₅H₂₈Cl₂N₂O₅.HCl Calculated C, 53.14 H, 5.62 N, 5.39 Found C, 51.51 H,5.41 N, 4.99 

TABLE 16 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 28

DMSO-d₆ 0.82(6H, d, J=6.0Hz) 1.74-1.90(4H, m) 2.80-2.95(2H, m)3.10-3.28(3H, m) 3.86(2H, d, J=6.0Hz) 4.06-4.10(2H, m) 4.70-4.78(1H, m)7.16-7.32(5H, m) 7.85(3H, brs) 8.19(1H, s) 9.45(1H, d, J=7.0Hz)13.37(1H, s) KBr 3385 2962 1721 1642 # 1585 1542 1458 1355 1218 497(free base, MH⁺) C₂₄H₃₀Cl₂N₂O₅.HCl Calculated C, 55.99 H, 5.85 N, 5.25Found C, 53.22 H, 5.94 N, 5.21 29

DMSO-d₆ 0.82(6H, d, J=6.7Hz) 1.75-1.90(5H, m) 2.54(3H, s) 2.90-3.30(4H,m) 3.85(2H, d, J=7.0Hz) 4.00-4.10(2H, m) 4.60-4.70(1H, m) 7.15-7.32(5H,m) 8.19(1H, s) 8.67(2H, brs) 9.50(1H, brs) 13.38(1H, s) KBr 3360 29611740 1640 1584 # 1460 511 (free base, MH⁺) C₂₅H₃₂Cl₂N₂O₅.HCl CalculatedC, 54.80 H, 6.07 N, 5.11 Found C, 54.59 H, 6.06 N, 4.98 

TABLE 17 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 30

DMSO-d₆ 1.35(9H, s) 1.70-1.94 2.77-3.01(2H, m) 3.05-3.18(2H, m)4.00-4.10(2H, m) 4.52-4.68(1H, m) 7.15-7.34(5H, m) 7.80-8.03(3H, brs)8.21(1H, s) 9.40(1H, brs) 13.44(1H, s) KBr 2977 1640 1586 1386 1153 497(free base, # MH⁺) C₂₄H₃₀Cl₂N₂O₅.HCl Calculated C, 53.99 H, 5.85 N, 5.25Found C, 53.83 H, 6.14 N, 5.07 31

DMSO-d₆ 0.81(3H, t, J=6.0Hz) 1.12-1.24(8H, m) 1.44-1.54(2H, m)1.78-1.89(4H, m) 2.53-2.57(3H, m) 2.91-2.98(2H, m) 3.10-3.25(2H, m)4.05(4H, t, J=6.0Hz) 4.68-4.75(1H, m) 7.16-7.35(5H, m) 8.20(1H, s)8.70-8.78(2H, m) 9.48(1H, d, J=9.0Hz) 13.40(1H, s) KBr # 3423 2957 28561741 1638 1584 1541 1461 1411 1364 1259 1226 553 free base, MH⁺)C₂₈H₃₆Cl₂N₂O₅.HCl Calculated C, 57.00 H, 6.66 N, 4.75 Found C, 56.96 H,6.83 N, 4.53 

TABLE 18 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 32

DMSO-d₆ 1.64-1.87(4H, m) 3.07-3.27(4H, m) 3.67(3H, s) 4.05(2H, t, J=6Hz)4.71-4.81(1H, m) 6.90-7.60(10H, m) 7.73(1H, t, J=6Hz) 8.20(1H, s)9.50(1H, d, J=9Hz) 13.35(1H, s) Neat 3348 1726 1644 1584 1456 497 (freebase, MH⁺) 33

DMSO-d₆ 1.14(3H, t, J=7.5Hz) 1.65-1.86(4H, m) 3.10-3.25(4H, m) 4.05(2H,t, J=6Hz) 4.11(2H, t, J=6Hz) 4.68-4.77(1H, m) 6.88-7.60(10H, m) 7.76(1H,t, J=6Hz) 8.22(1H, s) 9.49(1H, d, J=9Hz) 13.36(1H, s) Neat 3345 17211644 1584 1457 511 # (free base, MH⁺) 

TABLE 19 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 34

DMSO-d₆ 0.80-1.48(5H, m) 1.50-1.90(10H, m) 2.55(3H, t, J=5.3Hz) 2.96(1H,brs) 3.66(3h, s) 4.04-4.12(2H, m) 4.52-4.62(1H, m) 8.29(1H, s) 8.68(2H,brs) 9.31(1H, d, J=6.8Hz) 13.54(1H, s) KBr 3290 2925 1750 1584 1461 1225475 # (free base, MH⁺) C₂₂H₃₂Cl₂N₂O₅.HCl Calculated C, 51.62 H, 6.50 N,5.47 Found C, 51.65 H, 6.20 N, 5.73 35

DMSO-d₆ 2.58(3H, s) 2.98-3.13(4H, m) 3.59(3H, s) 3.74-3.83(4H, m)4.09(2H, t, J=6.0Hz) 4.66-4.74(1H, m) 7.20-7.28(7H, m) 7.53-7.69(1H, m)KBr 3424 2952 1743 1625 1542 1435 1209 1067 485 (MH⁺) 

TABLE 20 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 36

DMSO-d₆ 2.54-2.58(3H, m) 3.09-3.22(4H, m) 3.66(3H, s) 3.78(2H, t,J=5.2Hz) 3.83(2H, t, J=4.5Hz) 4.22(2H, t, J=4.5Hz) 4.72-4.80(1H, m)7.18-7.29(5H, m) 8.20(1H, s) 8.72(2H, m) 9.50(1H, d, J=6.5Hz) 13.36(1H,brds) KBr 2953 2749 1745 1639 #1584 1541 1468 1349 1220 485 (free base,MH⁺) C₂₂H₂₆Cl₂N₂O₆.HCl Calculated C, 50.64 H, 5.22 N, 5.37 Found C,50.64 H, 5.13 N, 5.27 37

CDCl₃ 2.65(6H, s) 2.96-3.15(2H, m) 3.19-3.32(2H, m) 3.74(3H, s)3.79-3.86(4H, m) 4.18(2H, t, J=6.0Hz) 5.09-5.13(1H, m) 7.12-7.14(2H, m)7.21-7.28(4H, m) 7.76(1H, s) 9.18(1H, brds) 499 (MH⁺) 

TABLE 21 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 38

CDCl₃ 1.25(3H, t, J=7.1Hz) 2.53(3H, s) 2.91-2.95(2H, m) 3.21-3.25(2H, m)3.62-3.66(2H, m) 3.78-3.82(2H, m) 4.10-4.18(4H, m) 5.11-5.17(1H, m)7.13-7.26(6H, m) 8.00(1H, s) 11.18(1H, brds) 499 (MH⁺) 39

DMSO-d₆ 1.13(3H, t, J=7.0Hz) 2.56(3H, brds) 3.10-3.26(4H, m) 3.76(2H, t,J=5.0Hz) 3.81-3.85(2H, m) 4.11(2H, q, J=7.0Hz) 4.21-4.25(2H, m)4.69-4.76(1H, m) 7.19-7.30(5H, m) 8.22(1H, s) 8.71(2h, m) 9.55-9.57(1H,m) 13.38(1H, brds) KBr 2978 1743 # 1638 1584 1540 1469 1348 1260 1214499 (free base, MH⁺) C₂₃H₂₈Cl₂N₂O₆.HCl Calculated C, 51.55 H, 5.45 N,5.23 Found C, 51.49 H, 5.44 N, 5.24 

TABLE 22 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 40

DMSO-d₆ 1.84(4H, brs) 2.54(3H, s) 2.95(2H, brs) 3.09-3.40(4H, m)3.33(3H, s) 3.50-3.60(2H, m) 4.05(2H, brs) 4.11(2H, t, J=6Hz)4.74-4.84(1H, m) 7.20-7.30(5h, m) 8.22(1H, s) 8.74(2H, brs) 9.50(1H, s)499 (free base, MH⁺) 41

DMSO-d₆ 1.03(3H, t, J=6.2Hz) 1.83(4H, brs) 2.53(3H, t, J=5.3Hz)2.80-3.60(6H, m) 4.05(2H, m) 4.20(2H, m) 4.76(1H, m) 7.20-7.40(5H, m)8.19(1H, s) 8.55-8.85(2H, m) 9.48(1H, br) 13.37(1H, s) 527 (free base,MH⁺) 

TABLE 23 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 42

DMSO-d₆ 1.72-1.94(4H, m) 2.55(3H, t, J=5.5Hz) 2.85-3.02(2H, m) 3.20(3H,s) 3.04-3.28(2H, m) 3.30-3.42(2H, m) 3.48-3.62(2H, m) 3.93-4.08(2H, m)4.09-4.21(2H, m) 4.77-4.84(1H, m) 7.18-7.35(5H, m) 8.20(1H, s) 8.67(2H,brs) 9.47(1H, d, J=5.0Hz) 13.37(1H, s) # 555 (free base, MH⁺) 43

DMSO-d₆ 1.20(3H, t, J=7.4Hz) 1.80-1.84(4H, m) 2.82-2.92(2H, m)3.14-3.32(2H, m) 4.00-4.04(2H, m) 4.12(2H, q, J=7.4Hz) 4.72(2H, s)4.76-4.88(1H, m) 7.16-7.34(5H, m) 7.91(2H, bs) 8.21(1H, s) 9.54(1H, d,J=8.8Hz) 13.33(1H, s) KBr 3426 2960 1751 # 1640 1585 1458 1178 527 (freebase, MH⁺) 

TABLE 24 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 44

DMSO-d₆ 1.11(9H, s) 1.77-1.91(4H, m) 2.54(3H, s) 2.75-3.25(4H, m)4.00-4.10(2H, m) 4.40-4.80(1H, m) 5.76(2H, s) 7.20-7.40(5H, m) 8.17(1H,s) 8.74(2H, brs) 9.55(1H, brs) 13.29(1H, s) Neat 2971 1754 1640 15841460 569 (free # base, MH⁺) C₂₇H₃₄Cl₂N₂O₇.HCl Calculated C, 53.52 H,5.82 N, 4.62 Found C, 53.34 H, 5.97 N, 4.39 45

DMSO-d₆ 1.15-1.90(14H, m) 2.82-2.93(2H, m) 3.10-3.24(2H, m)4.01-4.08(2H, m) 4.65-4.75(2H, m) 7.18-7.32(5H, m) 7.92(3H, brs)8.21(1H, s) 9.47(1H, d) 13.39(1H, brs) KBr 3422 2939 1718 1641 1585 1458523 (free #base, MH⁺) C₂₆H₃₂CL₂N₂O₅.HCl Calculated C, 55.77 H, 5.94 N,5.00 Found C, 55.37 H, 6.02 N, 4.86 

TABLE 25 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 46

DMSO-d₆ 1.13-1.92(10H, m) 2.55(3H, t, J=6.0Hz) 2.85-3.02(2H, m)3.08-3.26(2H, m) 4.00-4.11(2H, m) 4.60-4.71(2H, m) 7.25-7.34(5H, m)8.20(1H, s) 8.64(2H, brs) 9.43(1H, d, J=6.0Hz) 13.39(1H, s) KBr 29381641 1584 1458 1357 #1219 537 (free base, MH⁺) C₂₇H₃₄Cl₂N₂O₅.HClCalculated C, 56.50 H, 6.15 N, 4.88 Found C, 54.51 H, 5.63 N, 4.64 47

DMSO-d₆ 0.66-0.88(4H, m) 0.92-1.92(8H, m) 2.50(6H, d, J=3.0Hz)2.72-2.92(2H, m) 3.22-3.78(4H, m) 4.04-4.12(2H, m) 4.62-4.96(1H, m)7.22-7.42(6H, m) 8.20(1H, s) 9.44(1H, br) 13.43(1H, s) KBr 2929 17181642 1584 1458 1221 551 # (free base, MH⁺) 

TABLE 26 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 48

DMSO-d₆ 1.60-2.15(8H, m) 2.72(3H, s,) 2.80-3.60(6H, m) 4.05-4.10(2H, m)4.60-4.91(2H, m) 7.20-7.39(6H, m) 7.82(3H, brs) 8.19-8.26(1H, m) Neat2964 1740 1674 1584 1458 538 (free base, MH⁺) 49

DMSO-d₆ 1.40-1.53(2H, m) 1.65-1.96(16H, m) 2.82-2.93(2H, m,3.13-3.40(2H, m) 4.05(2H, t, J=6Hz) 4.74-4.88(2H, m) 7.08-7.16(5H, m)7.91(3H, brs) 8.21(1H, s) 9.48(1H, d, J=9Hz) 13.39(1H, s) KBr 3386 29091718 1642 1585 1541 # 1456 575 (free base, MH⁺) 

TABLE 27 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 50

DMSO-d₆ 175-1.91(4H, m) 2.54(3H, t, J=4.5Hz) 2.90-3.08(3H, m) 3.22(1H,dd, J=12, 3Hz) 3.82(2H, d, J=6Hz) 3.98-4.08(2H, m) 4.78-4.88(1H, m)7.12-7.37(5H, m) 8.27(1H, s) 8.64(1H, t, J=6Hz) 8.70(2H, brs) 9.30(1H,d, J=6Hz) #13.20(1H, brs) 13.52(1H, s) KBr 3398 2958 1736 1641 1585 1542512 (free base, MH⁺) 51

DMSO-d₆ 1.77-1.91(4H, m) 2.54(3H, t, J=6Hz) 2.95(2H, brs) 3.03(1H, dd,J=15, 12Hz) 3.22(1H, dd, J=15, 6Hz) 3.64(3H, s) 3.91(2H, d, J=6Hz)4.00-4.09(2H, m) 4.77-4.87(1H, m) 7.13-7.38(5H, m) 8.27(1H, s)8.70-8.87(3H, m) 9.34(1H, d, # J=9Hz) 13.52(1H, s) Neat 2951 1747 16611584 1556 526 (free base, MH⁺) 

TABLE 28 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 52

DMSO-d₆ 1.17(3H, t, J=6.0Hz) 1.62-1.92(4H, m) 2.77-2.97(4H, m) 3.09(1H,dd, J=15.0, 12.0Hz) 3.11-3.35(1H, m) 3.99-4.12(2H, m) 4.82-4.96(1H, m)7.13-7.36(5H, m) 7.92(2H, brs) 8.25(1H, s) 9.61-9.73(1H, m) 13.23(1H, s)KBr 2930 1641 1584 # 1535 1457 1226 485 (free base, MH⁺)C₂₂H₂₆Cl₂N₂O₄S.HCl Calculated C, 50.63 H, 5.21 N, 5.37 Found C, 50.40 H,5.29 N, 5.28 53

DMSO-d₆ 1.82(4H, m) 2.80(2H, m) 3.16(1H, dd, J=9, 12Hz) 3.24(1H, dd,J=6, 12Hz) 4.05(2H, brs) 4.81(1H, ddd, J=6, 7.9Hz) 5.14(1H, d, J=12Hz)5.17(1H, d, J=12Hz) 7.16-7.39(10H, m) 7.91(3H, brs) 8.19(1H, s) 9.50(1H,d, J=7Hz) 13.32(1H, s) KBr # 3397 2958 1719 1642 1586 1543 531 (freebase, MH⁺) C₂₇H₂₈Cl₂N₂O₅.HCl Calculated C, 57.11 H, 5.15 N, 4.93 FoundC, 56.97 H, 5.22 N, 5.15 

TABLE 29 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 54

DMSO-d₆ 1.84(4H, brs) 2.54(3H, t, J=6Hz) 2.95(2H, brs) 3.16(1H, d, J=10,12Hz) 3.25(1H, d, J=6, 12Hz) 4.05(2H, brs) 4.81(1H, ddd, J=6, 7, 9Hz)5.14(1H, d, J=12Hz) 5.17(1H, d, J=12Hz) 7.28-7.87 (10H, m) 8.19(1H, s)#8.75(2H, brs) 9.50(1H, d, J=7Hz) 13.32(1H, s) KBr 3412 3300 2958 27891745 1639 1584 1541 545 (free base, MH⁺) C₂₈H₃₀Cl₂N₂O₅.HCl Calculated C,57.79 H, 5.37 N, 4.81 Found #C, 57.34 H, 5.44 N, 4.78 55

DMSO-d₆ 1.76-1.95(4H, m) 2.75(6H, s) 3.05-3.30(4H, m) 4.06(2H, t, J=7Hz)4.75-4.87(1H, m) 5.10-5.20(2H, m) 7.18-7.40 (10H, m) 8.18(1H, s)9.52(1H, brs) 10.20(1H, brs) 13.40(1H, brs) KBr 2957 2690 1740 1638 1584#1456 558 (free base, MH⁺) C₂₉H₃₂Cl₂N₂O₅.HCl Calculated C, 58.45 H, 5.58N, 4.70 Found C, 58.18 H, 5.49 N, 4.72 

TABLE 30 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 56

DMSO-d₆ 1.82(4H, m) 2.95(2H, m) 3.08-3.55 (12H, m) 4.04(2H, brs)4.41(2H, m) 4.88(1H, m) 7.12-7.36 (5H, m) 7.97(3H, brs) 8.31(1H, s)9.63(3H, m) KBr 3423 2957 1751 1638 1585 1542 1458 553 (free base, #MH⁺) C₂₆H₃₄Cl₂N₄O₅.3HCl Calculated C, 47.11 H, 5.63 N, 8.45 Found C,45.84 H, 5.72 N, 7.76 57

DMSO-d₆ 1.42-1.86 (10H, m) 2.22-2.40 (4H, m) 2.72-2.84 (2H, m) 3.18-3.28(2H, m) 4.66-4.72 (1H, m) 7.16-7.34 (5H, m) 7.84(2H, br) 8.20, 8.22(1H,s) 9.34, 9.53(1H, d, J=5.8Hz) 13.32, 13.48(1H, s) KBr 3422 # 2937 17521639 1584 1541 1457 1346 1227 536 (free base, MH⁺) 

TABLE 31 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 58

DMSO-d₆ 2.81(3H, s) 3.13-3.80(10H, m) 4.27-4.47(2H, m) 4.66-4.83(1H, m)7.13-7.32(5H, m) 8.22(1H, s) 9.49(1H, d, J=8.5Hz) 13.71(1H, brs) KBr1740 1641 1584 1457 1355 1220 510 free base, MH⁺) #C₂₄H₂₉Cl₂N₃O₅.2HClCalculated C, 49.42 H, 5.36 N, 7.20 Found C, 47.94 H, 5.52 N, 6.77 59

DMSO-d₆ 1.15(3H, d, J=6.2Hz) 2.78-3.95(13H, m) 3.67(3H, s) 4.54-4.72(1H,m) 7.17-7.34(5H, m) 7.45(1H, s) 8.69-8.82(1H, m) 12.27-12.36(1H, m) 510(MH⁺) 

TABLE 32 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 60

DMSO-d₆ 1.30(3H, d, J=6Hz) 3.00-3.70(11H, m) 3.67(3H, s) 4.42(2H, s)4.75(1H, m) 7.18-7.30(5H, m) 8.23(1H, s) 9.52(1H, d, J=9Hz) 9.80(1H, br)13.39(1H, br) 510 (free base, MH⁺) 61

DMSO-d₆ 1.29(3H, d, J=6.3Hz) 3.00-3.20(9H, m) 3.66(3H, s) 4.41(2H, brs)4.77(1H, m) 7.15-7.30(5H, m) 8.22(1H, s) 9.49(1H, d, J=7.6Hz) 9.70(2H,br) 13.35(1H, brs) KBr 3427 1736 1641 1458 1222 510 (free base, MH⁺)Optical # rotation: [α]_(D) ²⁵ = −53.0⁺ (c = 0.37, MeOH) 

TABLE 33 ¹H-NMR Elemental Ex. δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 62

DMSO-d₆ 1.30(3H, d, J=6.0Hz) 3.09-3.83(11H, m) 3.67(3H, s) 4.34-4.47(2H,m) 4.73-6.81(1H, m) 7.17-7.29(5H, m) 8.23(1H, s) 9.51(1H, d, J=6.0Hz)9.63-9.92(1H, m) 13.35-13.47(1H, m) KBr 3425 2450 1747 1664 1452 1248#1213 510 (free base, MH⁺) C₂₄H₂₉Cl₂N₃O₅.2HCl Calculated C, 54.16 H,5.13 N, 6.11 Found C, 53.21 H, 5.25 N, 5.96 63

DMSO-d₆ 1.34(3H, d, J=8Hz) 2.80(3H, s) 3.00-3.70(11H, m) 3.67(3H, s)4.37(2H, brs) 4.75(1H, m) 7.15-7.32(5H, m) 8.22(1H, s) 9.50(1H, d,J=6Hz) 13.39(1H, s) 524 (free base, MH⁺) 

TABLE 34 Elemental Ex. ¹H-NMR δ (ppm), IR FAB- analysis No. Compound 300MHz (cm⁻¹) MS (%) 64

DMSO-d₆ 1.14(3H, t, J=7.6 Hz) 2.48-2.52(8H, m) 3.14-3.38 (4H, m)4.11(2H, q, J=7.6 Hz) 4.39(2H, bs) 4.68-4.80(1H, m) 7.18-7.32(5H, m)8.23(1H, s) 9.47(1H, d, J=8.8 Hz) KBr 2950 2784 1745 1637 1589 1544 14651369 1264 1097 #510 (free base, MH⁺) 65

DMSO-d₆ 1.11(3H, t, J=6.0 Hz) 2.60-3.20(13H, m) 4.00-4.10 (4H, m)4.62-4.66(1H, m) 7.20-7.30(5H, m) 7.75(1H, s) KBr 3422 2940 2360 17361638 1456 524 (MH⁺) 

TABLE 35 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 66

DMSO-d₆ 2.10-2.35 (2H, m) 2.80(3H, s) 3.10-3.94(12H, m) 3.66(3H, s)4.10-4.22 (2H, m) 4.62-4.72(1H, m) 7.20-7.41(5H, m) 8.20(1H, s) 9.47(1H,d, J=6.0 Hz) 13.3(1H, brs) KBr 3423 1740 1640 1584 1458 1356 1219 #524(free base, MH⁺) C₂₃H₃₁Cl₂N₃O₅.2HCl Calculated C, 50.27 H, 5.57 N, 7.03Found C, 49.88 H, 5.56 N, 6.93 67

DMSO-d₆ 1.14(3H, t, J=6.0 Hz) 2.23(2H, m) 3.00-3.05(10H, m)4.05-4.16(4H, m) 4.67-4.77(1H, m) 7.12-7.35(5H, m) 7.50-7.66(1H, m)8.21(1H, brs) 9.40-9.60(1H, brs) 9.45(1H, d, J=6.0 Hz) 13.40(1H, brs)#KBr 2361 2343 1584 1458 1352 1216 #524 (free base, MH⁺)C₂₅H₃₁Cl₂N₃O₅.2HCl Calculated C, 50.27 H, 5.57 N, 7.03 Found C, 49.68 H,5.68 N, 6.66 

TABLE 36 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 68

DMSO-d₆ 1.21(3H, t, J=8 Hz) 2.25(2H, brs) 2.82(3H, s) 3.08-3.90(12H, m)4.06-4.13 (4H, m) 4.70(1H, m) 7.16-7.28 (5H, m) 8.21(1H, s) 9.45(1H, d,J=8 Hz) 13.36(1H, brs) #538 (free base, MH⁺) 69

DMSO-d₆ 1.12(3H, t, J=6.9 Hz) 1.29-1.47(2H, m) 1.73(2H, dd, J=5.7, 12.0Hz) 1.80-1.95 (4H, m) 2.85(2H, m) 3.07-3.28 (4H, m) 4.04-4.13(4H, m)4.67-4.75(1H, m) 7.16-7.28 (5H, m) 8.20(1H, s) 8.65(1H, brs) 8.87(1H,brs) 9.50(1H, brs) 13.35(1H, brs) #KBr 3372 2940 2805 2726 2489 17391642 1585 1544 1460 1412 1360 1352 1219 #509 (free base, M⁺) 

TABLE 37 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 70

DMSO-d₆ 1.23(3H, t, J=7.1 Hz) 1.42-1.57 (2H, m) 1.68-1.98 (5H, m)2.69(3H, s) 2.88-2.96(2H, m) 3.10-3.24(2H, m) 3.31-3.39(2H, m)4.05-4.14(4H, m) 4.72(1H, ddd, J=6.3, 7.5, 9.1 Hz) 7.15-7.29 (5H, m)8.21(1H, s) 9.48(1H, d, J=7.5 Hz) 10.34(1H, brs) 13.35 (1H, brs) #KBr3406 2938 1736 1638 1584 1460 1412 1352 1215 1075  957  701 523 (freebase, MH⁺) 71

CDCl₃ 1.13(3H, t, J=7.0 Hz) 1.70-1.88 (4H, m) 2.49-2.53(5H, m)3.07-3.21(2H, m) 4.06-4.13(4H, m) 4.69 (1H, dd, J=8.4, 15.6 Hz) 6.67(1H,s) 7.18-7.32(5H, m) 8.04(1H, s) 8.75(1H, brs) 8.99(1H, d, J= 7.2 Hz)12.51(1H, brs) # 449.1 (free base, MH⁺) C₂₃H₃₀Cl₂N₂O₅.HCl Calculated C,56.91 H, 6.23 N, 5.77 Found C, 56.90 H, 6.29 N, 5.73 

TABLE 38 Ex. ¹H-NMR δ (ppm), IR Elemental No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 72

DMSO-d₆ 1.13(3H, t, J=7.0 Hz) 1.75-1.90(4H, brs) 2.74(3H, s) 2.75(3H, s)3.12-3.33(4H, m) 4.10(4H, m) 4.70 (1H, dd, J=4.3, 14.4 Hz) 6.65(1H, brs)7.21-7.29(5H, m) 8.04(1H, s) 8.98(1H, d, J=7.8 Hz) 12.51(1H, s) #KBr3428 2958 2686 1736 1637 1604 1541 1493 1375 1267 1198 463 (free base,MH⁺) 73

CDCl₃ 1.95-2.10(4H, m) 2.70(3H, s) 3.11(2H, t, J=7.5 Hz) 3.21(2H, m)3.77(3H, s) 4.01(2H, t, J=6.0 Hz) 5.00(1H, m) 6.38(1H, s) 7.02(1H, d,J=7.2 Hz) 7.14-7.32(5H, m) 7.52(1H, s) 9.43(2H, brs) 12.2(1H, s) #KBr1741 1637 1489 1265 479 free base, MH⁺) 

TABLE 39 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 74

DMSO-d₆ 1.13(3H, t, J=7.0 Hz) 1.70-1.89(4H, m) 2.87(2H, m) 3.2(2H, m)4.0-4.1(4H, m) 4.7(1H, m) 6.65(1H, s) 7.15-7.30(5H, m) 7.92(3H, brs)8.17(1H, s) 8.98(1H, d, J=5.6 Hz) 12.51(1H, s) #KBr 1736 1601 1489 13731263 479 (free base, MH⁺) C₂₂H₂₇BrN₂O₅.HCl Calculated C, 5.123 H, 5.47N, 5.43 Found C, 50.93 H, 5.51 N, 5.34 75

CDCl₃ 1.27(3H, t, J=7.2 Hz) 1.93-2.02(2H, m) 2.07-2.17(2H, m) 2.71(3H,s) 3.1-3.2(2H, m) 3.2-3.3(2H, m) 4.03(2H, t, J=6 Hz) 4.23(2H, q, J=7 Hz)4.98(1H, dt, J=7, 6 Hz) 6.39(1H, s) 6.88(1H, d, J=7.8 Hz) 7.14-7.18(2H,m) # 7.22-7.32(3H, m) 7.49(1H, m) 9.51(2H, brs) 12.29(1H, brs) KBr 33742960 1736 1638 1599 1376 1266 1199 #493 (free base, MH⁺) 

TABLE 40 Ex. IR No. Compound ¹H-NMR δ (ppm), 300 MHz (cm⁻¹) FAB-MSElemental analysis (%) 76

DMSO-d₆ 1.91(4H, m) 2.12(3H, s) 2.57(3H, s) 2.98(2H, m) 3.10-3.30(2H, m)3.70(3H, s) 3.99(2H, m) 4.78(1H, m) 6.35(1H, s) 7.15-7.30(5H, m)7.65(1H, s) 8.62(1H, brs) 9.24(2H, brs) 12.09(1H, s) 449 (free base, M− 1) 77

CDCl₃ 1.13(3H, t, J=7 Hz) 1.85-1.95(4H, m) 2.04(3H, s) 2.18(3H, s)2.51(3H, m) 2.93(2H, m) 3.16-3.20(2H, m) 3.76(2H, m) 4.10(2H, q, J=7 Hz)4.69(1H, m) 7.17-7.32(5H, m) 7.71(1H, s) 9.01(2H, brs) 9.07(1H, d, J=8Hz) 12.66(1H, s) 442 (free base, MH⁺) 

TABLE 41 Ex. IR No. Compound ¹H-NMR δ (ppm), 300 MHz (cm⁻¹) FAB-MSElemental analysis (%) 78

DMSO-d₆ 1.63-1.78(4H, m) 2.02(3H, s) 2.55(3H, s) 2.82-3.11(4H, m)3.62(3H, s) 3.84-3.95(2H, m) 4.58-4.65(1H, m) 6.21(1H, d, J=2.4 Hz)6.24(1H, d, J=2.4 Hz) 7.18-7.36(5H, m) 8.38(1H, d, J=7.5 Hz)8.62-8.78(2H, m) 9.70(1H, brs) 415 (free base, MH⁺) 79

DMSO-d₆ 1.80(4H, m) 2.50(3H, m) 2.95(2H, m) 3.08-3.22(2H, m) 3.65(3H, s)3.95-4.15(2H, m) 4.60-4.75(3H, m) 6.54(1H, s) 7.15-7.32(5H, m) 7.99(1H,s) 8.68(2H, brs) 8.93(1H, d, J=8 Hz) 12.54(1H, s) 432 (free base, MH⁺) 

TABLE 42 Ex. IR No. Compound ¹H-NMR δ (ppm), 300 MHz (cm⁻¹) FAB-MSElemental analysis (%) 80

DMSO-d₆ 1.71-1.83(4H, m) 2.02(3H, s) 2.55(3H, s) 2.88-3.11(4H, m)3.63(3H, s) 3.92-4.03(1H, m) 6.45(1H, s) 7.08-7.37(5H, m) 8.57-8.78(2H,m) 8.59(1H, d, J=7.8 Hz) 9.80(1H, brs) 493 (free base, MH⁺) 81

DMSO-d₆ 1.79-1.93(4H, m) 2.00(3H, s) 2.56(3H, s) 2.91-3.11(4H, m)3.63(3H, s) 3.83-3.95(2H, m) 4.60-4.66(1H, m) 7.20-7.36(5H, m)8.54-8.66(2H, m) 8.93(1H, d, J=7.8 Hz) 9.61(1H, s) 571 (free base, MH⁺) 

TABLE 43 Ex. No. Compound 82

83

¹H-NMR δ (ppm), IR FAB- Ex. No. 300 MHz (cm⁻¹) MS Elemental analysis (%)82 DMSO-d₆ 1.19 KBr 541 C₂₅H₃₀Cl₂N₂O₇.HCl (3H, t, J=7.1 Hz) 2961 (freeCalculated 1.83(4H, brs) 1750 base, C, 51.96 2.48-2.53(5H, m) 1461 MH⁺)H, 5.41 2.94(2H, brs) 1178 N, 4.85 3.16-3.34(5H, m) Found 4.02-4.18(4H,m) C, 51.88 4.76(2H, d, J=2.2 Hz) H, 5.40 4.84-4.92(1H, m) N, 4.827.16-7.36(5H, m) 8.22(1H, s) 8.87(2H, brs) 9.56(1H, d, J=7.2 Hz)13.31(1H, s) 83 DMSO-d₆ 1.32 KBr 603 C₃₀H₂₂O₇N₂O₃.HCl (3H, t, J=7.0 Hz)3426 (free Calculated 1.82(4H, brs) 2960 base, C, 56.31 2.57(3H, brs)1717 M⁺) H, 5.20 2.97(2H, brs) 1641 N, 4.38 4.06(2H, brs) 1604 Found4.32(2H, q, J=7.0 Hz) 1457 C, 54.81 4.99(1H, dd, J=5.7, 1278 H, 5.3014.1 Hz) 1162 N, 4.34 7.16-7.36(7H, m) 8.01(2H, d, J=8.7 Hz) 8.23(1H,brs) 8.33(2H, brs) 9.66(1H, brs) 11.3(1H, brs) 

TABLE 44 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 84

DMSO-d₆ 1.15(6H, t, J=7 Hz) 1.75-2.00(6H, m) 2.49(3H, s) 2.90-3.05(8H,m) 3.10-3.25(2H, m) 4.00-4.21(4H, m) 4.74(1H, m) 7.17-7.30(5H, m)8.28(1H, s) 8.88(2H, brs) 9.64(1H, brs) 10.43(1H, brs) 13.37(1H, brs)568 (free base, MH⁺) 85

DMSO-d₆ 1.28(12H, m) 1.84(4H, m) 2.53(3H, t, J=5.7 Hz) 2.94(2H, m)3.13-3.93(4H, m) 3.63(2H, m) 4.01(2H, m) 4.37-4.48(1H, m) 7.18-7.29(5H,m) 8.31(1H, s) 8.86(2H, brs) 9.70(1H, brs) 10.03(1H, brs) 13.37(1H, brs)582 (free base, MH⁺) 

TABLE 45 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 86

DMSO-d₆ 0.72-0.97(6H, m) 1.18-1.42(4H, m) 1.51-1.73(4H, m) 1.75-1.83(4H,m) 2.83-3.15(6H, m) 3.16-3.39(5H, m) 4.02-4.10(2H, m) 4.37-4.55(2H, m)4.75-4.91(1H, m) 7.20-7.30(5H, m) 8.36(1H, s) 8.68-8.96(2H, m)9.74-9.88(1H, m) 10.56-10.73(1H, m) # 13.32-13.47(1H, m) 610 (free base,MH⁺) 87

CDCl₃ 1.80-1.89(2H, m) 1.19-2.01(2H, m) 3.21(1H, dd, J=14, 6 Hz)3.28(1H, dd, J=14, 6 Hz) 3.76(2H, t, J=7 Hz) 3.80(3H, s) 4.12(2H, t, J=6Hz) 5.03(1H, ddd, J=8, 6, 6 Hz) 6.77(1H, d, J=8 Hz) 7.09-7.13(2H, m)7.28-7.35(3H, m) # 12.64(1H, s) 455 (free base, MH⁺) 

TABLE 46 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 88

DMSO-d₆ 1.70(2H, m) 1.85(2H, m) 2.04(2H, m) 2.62(3H, s) 2.93(2H, brs)3.18-3.20(2H, m) 3.76(3H, s) 5.01(1H, m) 6.65(1H, d, J=7 Hz) 6.78(1H, s)7.09-7.32(5H, m) 9.35(2H, brs) 11.87(1H, s) 384 (free base, MH⁺) 89

DMSO-d₆ 1.30(2H, m) 1.58(4H, m) 2.49(3H, s) 2.82(2H, t, J=8 Hz) 3.11(1H,dd, J=14, 9 Hz) 3.19(1H, dd, J=14, 6 Hz) 3.65(3H, s) 4.74(1H, m)6.75(2H, m) 7.18-7.31(5H, m) 7.81(1H, d, J=9 Hz) 8.75(2H, brs) 9.00(1H,d, J=8 Hz) 399 (free base, MH⁺) 

TABLE 47 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 90

CDCl₃ 1.25-1.45(4H, m) 1.55-1.64(2H, m) 1.77-1.87(2H, m) 2.54(2H, t,J=7.5 Hz) 2.64(3H, s) 2.90(2H, t, J=7.8 Hz) 3.23(2H, m) 6.63(2H, dd,J=8.1, 1.8 Hz) 6.77(1H, d, J=1.5 Hz) 6.88(2H, d, J=7.8 Hz) 7.10-7.32(6H,m) # 9.38(2H, brs) 11.90(1H, brs) 413 (free base, MH⁺) 

TABLE 48 ¹H-NMR δ (ppm), IR FAB- Elemental Ex. No. Compound 300 MHz(cm⁻¹) MS analysis (%) 91

CDCl₃ 1.45-1.65(4H, m) 1.90-2.00(2H, m) 2.67(3H, s) 2.86-2.90(2H, t,J=7.5 Hz) 2.80-3.05(2H, m) 3.18-3.31(2H, m) 3.80(3H, s) 5.00-5.05(1H, m)7.15(-7.32(6H, m) 9.48(2H, brs) 12.44(1H, s) KBr 3429 2949 1743 16411587 #467.0 (free base, MH⁺) C₂₃H₂₈Cl₂N₂O₄.HCl Calculated C, 54.83 H,5.80 N, 5.56 Found C, 54.63 H, 6.07 N, 5.48 92

DMSO-d₆ 1.36(2H, m) 1.45-1.65(4H, m) 2.49(3H, s) 2.82(2H, t, J=7 Hz)2.83(2H, m) 3.15(2H, m) 3.64(3H, s) 4.74(1H, m) 6.92(1H, s)7.16-7.31(5H, m) 7.93(1H, s) 8.76(2H, brs) 9.05(1H, d, J=8 Hz) 12.01(1H,s) 433 (free base, MH⁺) 

TABLE 49 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 93

CDCl₃ 1.28(3H, t, J=7.2 Hz) 1.40-1.51(2H, m) 1.57-1.67(2H, m)1.84-1.95(2H, m) 2.62-2.68(5H, m) 2.88-3.01(2H, m) 3.16-3.29(2H, m)4.24(2H, q, J=7.2 Hz) 4.99(1H, ddd, J=6.2, 6.2, 7.5 Hz) 6.77(1H, m)7.17-7.33(6H, m) 7.35(1H, s) 9.41(2H, brs) 11.67(1H, brs) #KBr 3422 29401738 1644 1538 1484 1407 1373 1207 1096 1027  700 447 (free base, MH⁺)94

CDCl₃ 1.27(3H, t, J=7.1 Hz) 1.34-1.46(2H, m) 1.61-1.71(2H, m)1.83-1.94(2H, m) 2.69(2H, t, J=7.5 Hz) 2.78(3H, s) 2.79(3H, s)2.92-3.00(2H, m) 3.18-3.30(2H, m) 4.22(2H, q, J=7.1 Hz) 4.99(1H, ddd,J=6.0, 6.0, 7.2 Hz) 6.88(1H, s) 7.12-7.18(3H, m) 7.23-7.34(3H, m) #7.42(3H, s) 11.60(1H, brs) 12.26(1H, brs) KBr 3423 2941 2693 1739 16441539 1483 1405 1372 1212 1095 1029  957  862  749  703 461 (free base,MH⁺) 

TABLE 50 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 95

CDCl₃ 1.4-1.6(4H, m) 1.90(2H, m) 2.50-2.66(5H, m) 2.94(2H, t, J=7.5 Hz)3.20(2H, m) 5.02(1H, s) 6.77(1H, s) 7.16-7.36(6H, m) 7.54(1H, s)9.38(2H, brs) 11.57(1H, brs) #KBr 3375 1744 1641 1604 1540 477 (freebase, MH⁺) 96

CDCl₃ 1.47-1.60(4H, m) 1.96(2H, m) 2.68(3H, s) 2.94(4H, m) 3.24(2H, dt,J=7.8, 6.3 Hz) 3.80(3H, s) 5.05(1H, q, J=6.9 Hz) 7.14-7.34(6H, m)7.50(1H, s) 557 (free base, MH⁺) 

TABLE 51 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 97

CDCl₃ 1.45(2H, m) 1.55(2H, m) 1.87(2H, m) 2.46(3H, s) 2.67(3H, m)2.80(2H, m) 2.94(2H, m) 3.19(1H, dd, J=14, 7 Hz) 3.30(1H, dd, J=14, 5Hz) 3.80(3H, s) 5.00(1H, ddd, J=8, 7, 5 Hz) 6.74(1H, s) 7.16-7.34(5H, m)7.83(1H, d, J=8 Hz) 7.93(1H, s) 9.31(2H, brs) # 11.84(1H, brs) 441 (freebase, MH⁺) 98

DMSO-d₆ 1.19(3H, t, J=7 Hz) 1.30-1.63(6H, m) 2.85-2.90(5H, m) 3.17(1H,dd, J=14, 11 Hz) 3.21(1H, dd, J=14, 5 Hz) 4.14(2H, q, J=7 Hz) 4.77(2H,q, J=16 Hz) 4.88(1H, m) 7.17-7.34(5H, m) 8.13(1H, s) 8.60(2H, brs)9.55(1H, d, J=8 Hz) 13.14(1H, s) # 539 (free base, MH⁺) 

TABLE 52 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%)  99

CDCl₃ 1.38(3H, t, J=6.9 Hz) 1.40-2.0(6H, m) 2.65(3H, s) 2.80-3.00(4H, m)3.38(2H, d, J=6.3 Hz) 4.37(2H, q, J=7.0 Hz) 5.22(2H, q, J=7.2 Hz)7.08(2H, d, J=8.7 Hz) 7.23-7.38(7H, m) 8.07(2H, d, J=8.9 Hz) 9.44(2H,brs) 601 (free base, MH⁺) 100

DMSO-d₆ 1.13(3H, t, J=9 Hz) 1.20-1.60(7H, m) 1.80-1.87(2H, m) 2.70(3H,s) 2.80-2.95(4H, m) 3.10-3.40(4H, m) 4.11(2H, q, J=9 Hz) 4.70(1H, m)7.18-7.30(5H, m) 8.11(1H, s) 9.47(1H, d, J=8 Hz) 9.75(1H, brs) 13.15(1H,brs) 521 (free base, MH⁺) 

TABLE 53 ¹H-NMR δ (ppm), IR FAB- Elemental Ex. No. Compound 300 MHz(cm⁻¹) MS analysis (%) 101

DMSO-d₆ 1.15(3H, t, J=7.0 Hz) 1.20-1.40(4H, m) 1.45-1.65(3H, m)1.73-1.85(2H, m) 2.51(2H, s) 2.70-2.90(2H, m) 3.10-3.30(4H, m) 4.11(2H,q, J=7.0 Hz) 4.72(1H, dd, J=6.0, 14.0 Hz) 7.15-7.30(5H, m) 8.13(1H, s)8.87(1H, brs) 9.49(1H, brd, J=6.0 Hz) 13.2(1H, brs) # 507 (free base,MH⁺) 102

1.12(3H, t, J=7.1 Hz) 1.95(2H, brs) 2.92(2H, t, J=7.5 Hz) 3.09-3.78(12H,m) 4.10(2H, q, J=7.1 Hz) 4.71(1H, ddd, J=6.0, 7.2, 9.3 Hz) 7.17-7.28(5H,m) 8.16(1H, s) 9.51(1H, d, J=7.2 Hz) 9.64(2H, brs) 11.79(1H, brs)13.20(1H, brs) #KBr 3396 2933 2656 1734 1644 1589 1543 1455 1405 13721254 1214 1099 1014  701 508.0 (free base, MH⁺) 

TABLE 54 Ex. ¹H-NMR δ (ppm), IR Elemental No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 103

DMSO-d₆ 1.13(3H, t, J=7.2 Hz) 1.77-2.12(6H, m) 2.85-3.27(7H, m) 3.48(1H,brd, J=8.6 Hz) 4.10(2H, q, J=7.2 Hz) 4.67-4.78(1H, m) 7.19-7.28(5H, m)8.15(1H, s) 8.22(3H, brs) 9.49(1H, brd, J=7.1 Hz) 10.27(1H, brs)13.22(1H, brs) 522.1 (free base, MH⁺) 104

CDCl₃ 0.90-2.05(20H, m) 2.50-2.70(5H, m) 2.96(2H, m) 3.82(1H, s)4.82(1H, m) 6.68(1H, s) 7.45(1H, s) 7.52(1H, d, J=8.1 Hz) 439 (freebase, MH⁺) 

TABLE 55 Ex. ¹H-NMR δ (ppm), IR Elemental No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 105

DMSO-d₆ 1.87(4H, bs) 2.52(3H, d, J=8.5 Hz) 2.86-3.02(4H, m)3.04-3.14(1H, m) 3.48(3H, s) 4.09(2H, bs) 4.42-4.62(1H, m) 7.14-7.32(5H,m) 7.54(1H, s) 7.56-7.68(2H, m) 7.72-7.82(1H, m) 8.02(2H, d, J=7.6 Hz)9.04(1H, d, J=7.6 Hz) 568 (free base, MH⁺) 106

DMSO-d₆ 1.84(4H, s) 2.17(3H, s) 2.55(2H, s) 2.95-3.10(4H, m) 3.40(3H, s)3.65(3H, s) 4.05(2H, s) 4.63(1H, m) 7.20-7.35(5H, m) 7.50(1H, s)8.66(1H, brs) 8.91(1H, d, J=9.0 Hz) 511 (free base, MH⁺) 

TABLE 56 Ex. ¹H-NMR δ (ppm), IR Elemental No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 107

DMSO-d₆ 1.15(3H, d, 6.0 Hz) 1.17(3H, d, J=6.0 Hz) 1.40-1.90(4H, m)2.50-2.58(3H, m) 2.65-2.73(1H, m) 2.90-3.17(3H, m) 3.63(3H, s)4.00-4.05(2H, m) 4.55-4.62(1H, m) 7.20-7.33(5H, m) 7.44(1H, s)8.70-8.85(2H, m) 8.95(1H, d, J=7.0 Hz) #KBr 3285 2950 2723 1768 17451648 539 (free base, MH⁺) C₂₆H₃₂Cl₂N₂O₆.HCl Calculated C, 54.22 H, 5.78N, 4.66 Found C, 54.24 H, 5.75 N, 4.83 108

DMSO-d₆ 1.22(9H, s) 1.78-1.90(4H, m) 2.53(3H, m) 2.90-3.03(3H, m)3.13(1H, dd, J=13.82, 5.53 Hz) 3.62(3H, s) 4.00-4.08(2H, m)4.53-4.60(1H, m) 7.20-7.32(5H, m) 7.38(1H, s) 8.82(2H, brs) 8.97(1H, d,J=7.80 Hz) Neal 2957 1749 1666 1456 #553 (free base, MH⁺) 

TABLE 57 Ex. ¹H-NMR δ (ppm), IR Elemental No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 109

DMSO-d₆ 1.90-1.97(4H, m) 2.53(3H, t, J=6 Hz) 2.99-3.12(7H, m) 3.16(1H,dd, J=12, 6 Hz) 3.66(3H, s) 4.00-4.10(2H, m) 4.56-4.65(1H, m)7.20-7.34(5H, m) 7.57(1H, s) 8.12(3H, brs) 8.88(2H, brs) 9.08(1H, d, J=6Hz) KBr 3422 2954 1741 1646 1456 #540 (free base, MH⁺) 110

DMSO-d₆ 1.84(4H, bs) 2.11(3H, s) 2.49(2H, bs) 2.88-3.22(4H, m) 3.63(3H,s) 4.05(2H, bs) 4.52-4.68(1H, m) 4.82(2H, bs) 7.12-7.34(5H, m) 7.54(1H,s) 8.85(2H, br) 8.99(1H, d, J=7.6 Hz) 571 (free base, M⁺H) 

TABLE 58 ¹H-NMR δ (ppm), IR Elemental Ex. No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 111

DMSO-d₆ 1.89-1.96(4H, m) 2.54(3H, brs) 2.65-2.82(4H, m) 2.90-3.05(3H, m)3.14(1H, dd, J=15.3 Hz) 3.62(3H, s) 4.00-4.08(2H, m) 4.57-4.65(1H, m)5.12(2H, s) 7.18-7.04(10H, m) 7.50(1H, s) 8.77(2H, brs) 8.94(3H, d, J=9Hz) #Neal 2954 2728 1778 1739 1667 659 (free base, MH⁺) 112

DMSO-d₆ 1.1-1.9(14H, m) 2.49-2.51(1H, m) 2.54(3H, s) 2.93-3.17(4H, m)3.63(3H, s) 4.0-4.10(2H, m) 4.55-4.15(1H, m) 7.23-7.32(5H, m) 7.44(1H,s) 8.72(1H, brs) 8.95(1H, d, J=7.0 Hz) KBr 3422 2935 1745 1654 1452 #579(free base, MH⁺) C₂₀H₂₆Cl₂N₂O₆.HCl Calculated C, 56.55 H, 6.05 N, 4.55Found C, 56.17 H, 6.16 N, 4.48 

TABLE 59 ¹H-NMR δ (ppm), IR Elemental Ex. No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 113

DMSO-d₆ 1.78-1.96(4H, m) 2.75(6H, brs) 2.95(1H, dd, J=15, 9 Hz)3.05-3.16(3H, m) 3.48(3H, s) 4.10(2H, t, J=6 Hz) 4.48-4.56(1H, m)7.17-7.29(5H, m) 7.49-7.65(3H, m) 7.73-7.81(1H, m) 8.00-8.05(2H, m)9.04(1H, d, J=6 Hz) 10.05(1H, brs) #Neal 2953 1747 1663 1453 587 (freebase, MH⁺) 114

DMSO-d₆ 1.8-1.9(4H, m) 2.53(3H, s) 2.80-3.15(4H, m) 3.32(3H, s) 3.51(3H,s) 4.05-4.10(2H, m) 4.51-4.60(1H, m) 7.19-7.61(9H, m) KBr 3433 2948 27191744 1645 1457 587 (free base, MH⁺) #C₃₀H₃₂Cl₂N₂O₆.HCl Calculated C,57.71 H, 5.33 N, 4.49 Found C, 57.75 H, 5.31 N, 4.47 

TABLE 60 ¹H-NMR δ (ppm), IR Elemental Ex. No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 115

DMSO-d₆ 1.76-1.94(4H, m) 2.23(3H, s) 2.30(6H, s) 2.50-2.58(3H, m)2.86-3.03(3H, m) 3.11(1H, dd, J=13.5, 6.0 Hz) 3.56(3H, s) 4.02-4.12(2H,m) 4.52-4.63(1H, m) 6.98(2H, s) 7.13-7.31(5H, m) 7.41(1H, s) 8.69(1H,brs) 9.08(1H, d, J=6.0 Hz) #KBr 1748 1455 1211 1057 615 (free base, MH⁺)C₂₂H₃₆Cl₂N₂O₆.HCl Calculated C, 58.95 H, 5.72 N, 4.30 Found C, 58.95 H,5.98 N, 4.21 116

DMSO-d₆ 1.26(3H, t, J=7.6 Hz) 1.85(4H, bs) 2.56(3H, t, J=5.6 Hz)2.84-3.22(4H, m) 3.64(3H, s) 4.06(2H, bs) 4.22(2H, q, J=7.6 Hz)4.58-4.66(1H, m) 7.20-7.38(5H, m) 7.54(1H, s) 8.76(2H, brs) 9.01(1H, d,J=8.2 Hz) #KBr 3423 2955 1774 1746 1669 1247 1215 1029 541 (free base,MH⁺) 

TABLE 61 ¹H-NMR δ (ppm), IR FAB- Elemental Ex. No. Compound 300 MHz(cm⁻¹) MS analysis (%) 117

DMSO-d₆ 1.15(3H, t, J=6.0 Hz) 1.76-1.91(4H, m) 2.17(3H, s) 2.50-2.59(3H,m) 2.90-3.07(3H, m) 3.14(1H, dd, J=6.0, 15.0 Hz) 4.00-4.15(4H, m)4.55-4.62(1H, m) 7.20-7.33(5H, m) 7.51(1H, s) 8.69(2H, brs) 8.89(1H, d,J=9.0 Hz) #KBr 1646 1528 1456 1372 1190 525 (free base, MH⁺)C₂₅H₃₀Cl₂N₂O₆.HCl Calculated C, 53.44 H, 5.56 N, 4.99 Found C, 52.79 H,5.46 N, 4.94 118

DMSO-d₆ 0.95-1.02(3H, d, J=6.0 Hz) 1.03-1.12(3H, d, J=6.0 Hz)1.78-1.92(4H, m) 2.18(3H, s) 2.51-2.59(3H, brs) 2.39-3.17(3H, m)3.11(1H, dd, J=13.5, 6.0 Hz) 4.00-4.12(2H, m) 4.48-4.60(1H, m) 4.88(1H,a, J=12.0, 6.0 Hz) 7.19-7.36(5H, m) 7.52(1H, s) 8.74(1H, brs) # 8.77(1H,d, J=9.0 Hz) KBr 1734 1655 1456 1373 1201 539 (free base, MH⁺)C₂₆H₃₂Cl₂N₂O₆.HCl Calculated C, 54.22 H, 5.78 N, 4.86 Found C, 54.04 H,5.68 N, 5.01 

TABLE 62 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 119

DMSO-d₆ 1.00(3H, d, J=6 Hz) 1.04(3H, d, J=6 Hz) 1.75-1.90(4H, m)2.82-3.09(4H, m) 4.05-4.12(2H, m) 4.40-4.50(1H, m) 4.70-4.85(1H, m)7.05-8.05(14H, m) 9.02(1H, d, J=7.0 Hz) KBr 3420 2980 1749 1669 15221452 #539 (free base, MH⁺) C₃₀H₃₂Cl₂N₂O₆.HCl Calculated C, 57.75 H, 5.33N, 4.49 Found C, 56.70 H, 5.21 N, 4.36 120

DMSO-d₆ 1.00(3H, d, J=6 Hz) 1.04(3H, d, J=6 Hz) 1.80-1.93(4H, m)2.54(3H, t, J=6 Hz) 2.90-3.00(3H, m) 3.05(1H, dd, J=15, 6 Hz)4.05-4.13(2H, m) 4.40-4.50(1H, m) 4.74-4.81(1H, m) 7.17-7.29(5H, m)7.55-7.63(3H, m) # 7.73-7.80(1H, m) 8.00-8.05(2H, m) 8.74(2H, brs)9.02(1H, d, J=9 Hz) Neal 2980 1746 1668 1453 601 (free base, MH⁺) 

TABLE 63 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 121

DMSO-d₆ 1.28(3H, d, J=6.40 Hz) 2.17(3H, s) 2.90-3.90 (11H, m)4.38-4.40(2H, m) 4.45-4.61(1H, m) 7.15-7.30(5H, m) 7.52(1H, s) 7.75(1H,d, J=7.0 Hz) 9.50-9.80(2H, m) #537 (free base, MH⁺) 122

DMSO-d₆ 1.29(3H, d, J=6.3 Hz) 2.18(1H, s) 3.02(1H, d, J=15.0, 8.5 Hz)3.16(1H, d, J=15.0 6.0 Hz) 2.90-3.80(9H, m) 3.65(3H, s) 4.31-4.48(2H, m)4.55-4.68(1H, m) 7.18-7.37(5H, m) 7.52(1H, s) 8.92(1H, d, J=14.0 Hz)9.58(2H, brs) #KBr 3422 1742 1664 1455 1368 1188 1151 551 (free base,MH⁺) C₂₄H₃₁Cl₂N₃O₆.2HCl Calculated C, 49.94 H, 5.32 N, 6.72 Found 48.39H, 5.16 N, 6.46 

TABLE 64 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 123

DMSO-d₆ 1.29(3H, d, J=6.3 Hz) 2.95(1H, dd, J=9.9 13.8 Hz) 3.09(1H, dd,J=9.9, 13.8 Hz) 3.20- 3.80(8H, m) 3.48(3H, s) 4.44(1H, brs)4.49-4.55(2H, m) 7.18-7.28(5H, m) 7.56(1H, s) 7.62(2H, t, J=7.8 Hz)7.78(1H, t, J=7.5 Hz) 7.53(2H, d, J=8.4 Hz) # 9.06(1H, d, J=7.8 Hz) KBr3430 1747 1664 614 (free base, MH⁺) Optical rotation: [α]²⁵ _(D) =−26.8° (c = 1.01, MeOH) 124

DMSO-d₆ 1.29(3H, d, J=6.2 Hz) 2.95(1H, dd, J=13.8, 9.8 Hz) 3.09(1H, dd,J=13.8, 5.4 Hz) 3.12-3.93(9H, m) 3.48(3H, s) 4.42-4.57(3H, m)7.18-7.29(5H, m) 7.56-7.64(3H, m) 7.75-7.80(1H, m) 8.01-8.04(2H, m)9.05(1H, d, J=7.8 Hz) 9.55-9.87(2H, m) #KBr 3422 1741 1642 1585 14581357 1221 614 (free base, MH⁺) C₃₁H₃₃Cl₂N₅O₆.2HCl Calculated C, 49.42 H,5.36 N, 7.20 Found 48.47 H, 5.58 N, 6.91 

TABLE 65 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 125

DMSO-d₆ 1.15(3H, t, J=7.3 Hz) 2.18(3H, s) 2.80(3H, s) 3.02(1H, dd,J=9.5, 13.8 Hz) 3.14(1H, dd, J=5.7, 13.8 Hz) 3.15-3.68(10H, m) 4.09(2H,q, J=7.3 Hz) 4.38(2H, bs) 4.59(1H, ddd, J=5.7, 9.5, 7.6 Hz)7.23-7.33(5H, m) 7.53(1H, s) 8.91(1H, d, J=7.6 Hz) #KBr 3433 2984 24181769 1735 1666 1529 1456 1378 1195 1064 566 (free base, MH⁺) 

TABLE 66 ¹H-NMR δ (ppm), IR Elemental Ex. No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 126

DMSO-d₆ 1.83(4H, bs) 2.54(3H, t, J=5.61 Hz) 2.95(2H, bs) 3.08-3.78(2H,m) 4.05(2H, bs) 4.62-4.72(1H, m) 7.20-7.38(5H, m) 8.21(1H, s) 8.70(2H,bs) 9.36(1H, d, J=7.7 Hz) 13.47(1H, s) #455 (free base, MH⁺) 127

DMSO-d₆1.69-1.92(4H, m) 2.79-2.96(2H, m) 3.09(1H, dd, J=15.0, 10.5 Hz)3.26(1H, dd, J=15.0, 6.6 Hz) 3.96-4.11(2H, m) 4.63-4.77(1H, m)7.13-7.35(5H, m) 7.86(3H, brs) 8.20(1H, s) 9.35(1H, d, J=9.0 Hz)12.10(1H, brs) 13.46(1H, s) #KBr 2971 1638 1585 1541 1457 1221 441 (freebase, MH⁺) C₂₀H₂₂Cl₂N₂O₅.HCl Calculated C, 50.27 H, 4.85 N, 5.86 FoundC, 50.22 H, 5.16 N, 5.47 

TABLE 67 Ex. ¹H-NMR δ (ppm), IR Elemental No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 128

DMSO-d₆ 1.70-1.90(4H, m) 2.76(6H, s) 3.10-3.40(4H, m) 4.04-4.08(2H, t,J=7 Hz) 4.60-4.75(1H, m) 7.19-7.30(5H, m) 8.18(1H, s) 9.41(1H, brs) KBr3422 1735 1638 1584 1458 469 (free base, MH⁺) 129

CD₃CO₂D 1.51(3H, s) 3.10-3.40(2H, m) 3.70-4.30(9H, m) 4.51-4.60(2H, m)5.09-5.06(2H, m) 7.29-7.21(5H, m) 7.94(1H, s) KBr 3418 2941 1734 16411457 495 (free base, MH⁺) #C₂₃H₂₇Cl₂N₃O₅.2HCl Calculated C, 48.52 H,5.13 N, 7.18 Found C, 47.55 H, 5.02 N, 6.72 

TABLE 68 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 130

DMSO-d₆ 1.28-1.38(2H, m) 1.50-1.64(4H, m) 2.50(3H, s) 2.62(2H, t, J=7.5Hz) 2.80-2.89(2H, m) 3.07(1H, dd, J=8.9, 13.9 Hz) 3.20(1H, dd, J=4.8,13.9 Hz) 4.69(1H, ddd, J=4.8, 7.8, 8.9 Hz) 6.89(1H, s) 7.12-7.30(5H, m)7.94(1H, s) 8.59(2H, brs) 8.98(1H, d, J=7.8 Hz) # 12.05(1H, brs)12.98(1H, brs) KBr 3368 2940 1733 1639 1543 1485 1408 1357 1258 1203 701 419 (free base, MH⁺) 131

DMSO-d₆ 1.25-1.40(2H, m) 1.50-1.70(4H, m) 2.80-2.70(8H, m) 2.94-3.40(4H,m) 4.68(1H, m) 5.90(1H, s) 7.09-7.20(5H, m) 7.95(1H, s) 8.97(1H, brs)433 (free base, MH⁺) 

TABLE 69 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 132

DMSO-d₆ 1.32-1.64(6H, m) 2.85(4H, m) 3.12-3.34(2H, m) 3.57(3H, s)4.68-4.72(1H, m) 7.16-7.30(5H, m) 8.13(1H, s) 8.65(2H, brs) 9.38(1H, d,J=7.4 Hz) 13.14(1H, brs) 453 (free base, MH⁺) 133

DMSO-d₆ 1.35(2H, m) 1.45-1.6(4H, m) 2.59(6H, s) 2.75(2H, m) 2.83(2H, m)2.96(1H, dd, J=9, 14 Hz) 3.13(1H, dd, J=5, 14 Hz) 4.62(1H, dd, J=5, 8Hz) 7.15-7.2(2H, m) 7.2-7.3(4H, m) 7.60(1H, s) 467 (free base, MH⁺) 

TABLE 70 Ex. ¹H-NMR δ (ppm), IR Elemental No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 134

DMSO-d₆2.79(3H, s) 3.04-4.10(12H, m) 4.33(2H, brs) 4.70(1H, m)7.17-7.30(5H, m) 8.21(1H, s) 9.36(1H, d, J=8 Hz) 13.47(1H, brs) 496(free base, MH⁺) 135

DMSO-d₆ 1.36(2H, m) 1.69(2H, dd, J=6.3, 12.6 Hz) 1.75-2.0(3H, m)2.67(3H, s) 2.87(2H, m) 2.95(1H, dd, J=8.4, 14.5 Hz) 3.11(1H, dd, J=5.4,14.1 Hz) 3.93(2H, t, J=6.3 Hz) 4.64(1H, dd, J=5.7, 7.5 Hz) 7.17-7.29(5H,m) 7.59(1H, s) 11.72(1H, brs) #495 (free base, MH⁺) 

TABLE 71 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 136

DMSO-d₆ 1.44-1.69(4H, m) 2.50-2.57(3H, m) 2.63-2.92(2H, m) 3.11(1H, dd,J=13.5, 9.0 Hz) 3.21(1H, dd, J=13.5, 6.6 Hz) 3.48-3.59(2H, m) 3.05(3H,s) 4.67-4.79(1H, m) 5.63(1H, brs) 7.17-7.34(5H, m) 8.02(1H, s) 8.57(2H,brs) 9.18(1H, d, J=9.0 Hz) 13.43(1H, s) #468 (free base, MH⁺) 137

DMSO-d₆1.29-1.84(8H, m) 2.69(3H, s) 2.88-3.36(6H, m) 3.73(3H, s)4.82-4.96(1H, m) 6.93(1H, d, J=8.5 Hz) 7.18-7.34(6H, m) 7.93(1H, t,J=4.2 Hz) KBr 3422 2939 1741 1638 1542 428 (free base, M⁺H) 

TABLE 72 ¹H-NMR δ (ppm), IR Elemental Ex. No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 138

DMSO-d₆ 1.83(4H, bs) 2.82-2.94(2H, m) 3.16-3.32(2H, m) 4.02-4.06(2H, m)4.88-5.02(1H, m) 7.06-7.42(8H, m) 7.62(2H, d, J=8.1 Hz) 7.86(2H, bs)8.32(1H, s) 10.38(1H, s) KBr 3412 2954 1638 1599 1542 1445 1066 #516(free base, MH⁺) 139

DMSO-d₆ 1.74-1.87(4H, m) 2.83-2.92(2H, m) 2.95-3.03(1H, m) 3.14-3.22(1H,m) 3.99-4.06(2H, m) 4.65-4.74(1H, m) 7.14-7.34(6H, m) 7.68-7.81(4H, m)8.23(1H, s) 9.19-9.21(1H, m) 13.56(1H, s) #KBr 2955 1677 1458 1413 13521261 1203 1138 440 (free base, MH⁺) C₂₀H₂₃Cl₂N₃O₄.HCl Calculated C,50.38 H, 5.07 N, 8.81 Found C, 47.87 H, 4.6 N, 7.31 

TABLE 73 Ex. No. Compound 140

141

¹H-NMR δ (ppm), IR FAB- Elemental Ex. No. 300 MHz (cm⁻¹) MS analysis (%)140 DMSO-d₆ KBr 454 C₂₂H₂₅Cl₂N₃O₄.HCl 1.80-1.84(4H, m) 3422 (freeCalculated 2.62(3H, d, J=4.5 Hz) 2940 base, C, 51.39 2.85-2.89(2H, m)1641 MH⁺) H, 5.34 3.00(1H, dd, J=13.7, 10.8 Hz) 1584 N, 8.56 3.16(1H,dd, J=13.7, 4.2 Hz) 1458 Found 4.00-4.16(2H, m) 1412 C, 50.034.66-4.73(1H, m) 1348 H, 5.38 7.13-7.32(5H, m) 1228 N, 8.157.82-7.97(3H, m) 8.20(1H, q, J=4.5 Hz) 8.27(1H, s) 9.31(1H, d, J=8.2 Hz)13.56(1H, s) 141 DMSO-d₆ KBr 534 1.78-1.86(4H, m) 2954 (free2.78-2.94(2H, m) 1670 base, 3.18-3.78(2H, m) 1639 MH⁺) 4.02-4.10(2H, m)1542 4.86-4.96(1H, m) 1508 7.12-7.42(8H, m) 1217 7.60-7.66(2H, m) 10657.32(2H, bs) 8.32(1H, s) 9.42(1H, d, J=8.8 Hz) 10.44(1H, s) 

TABLE 74 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 142

DMSO-d₆1.73- 1.88(4H, m) 2.79-2.92(2H, m) 3.08-3.30(2H, m) 4.01-4.07(2H,m) 5.02-5.32(1H, m) 7.17-7.21(2H, m) 7.26-7.31(2H, m) 7.45-7.47(2H, m)7.84-8.08(5H, m) 8.30(1H, s) 8.37(1H, d, J=6.0 Hz) 9.40(1H, d, J=9.0 Hz)11.24(1H, s) 13.42(1H, s) #KBr 3423 2957 1643 1572 1541 1439 1337 12601228 517 (free base, MH⁺) C₂₅H₂₆Cl₂N₄O₄.HCl Calculated C, 50.87 H, 4.78N, 9.49 Found C, 49.81 H, 5.14 N, 9.27 143

DMSO-d₆1.70- 1.90(4H, m) 2.58(3H, s) 2.75-3.00(4H, m) 3.88-3.98(2H, m)4.56-4.59(1H, m) 7.16-7.33(5H, m) 7.55(1H, s) 8.78(1H, m) KBr 3422 16241570 1542 1431 470 (MH⁺) 

TABLE 75 ¹H-NMR δ (ppm), IR Elemental Ex. No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 144

DMSO-d₆ 1.80-1.86(4H, m) 2.35(3H, s) 2.84-2.90(2H, m) 3.34-3.47(2H, m)4.00-4.06(2H, m) 5.56-5.64(2H, m) 7.19-7.34(5H, m) 7.96(3H, brs)8.22(1H, s) 9.86(1H, d, J=9 Hz) 13.19(1H, brs) KBr 3421 2935 1638 15881542 1457 #470 (free base, MH⁺) 145

DMSO-d₆ 1.70-1.92(4H, m) 2.73-3.01(4H, m) 3.42-3.58(2H, m) 3.95-4.11(2H,m) 4.13-4.32(1H, m) 4.97(1H, brs) 7.09-7.33(5H, m) 7.91(3H, brs)8.25(1H, s) 8.92(1H, d, J=9.0 Hz) 13.98(1H, s) KBr 3421 2950 1637 15831458 #427 (free base, MH⁺) C₂₀H₂₄Cl₂N₂O₄.HCl Calculated C, 51.80 H, 5.43N, 6.04 Found C, 50.96 H, 5.46 N, 5.65 

TABLE 76 ¹H-NMR δ (ppm), IR Elemental Ex. No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 146

DMSO-d₆ 1.58-1.82(4H, m) 2.68-2.84(2H, m) 3.02-3.26(2H, m) 3.67(3H, s)4.12-4.20(2H, m) 4.82-4.88(1H, m) 6.92(1H, d, J=9.0 Hz) 7.16-7.40(8H, m)7.54(1H, s) # 7.81(2H, br) 8.21(1H, s) 8.62(1H, d, J=7.2 Hz) 10.21(1H,s) KBr 3386 2952 1741 1647 1618 1527 1227 1188 437 (free base, MH⁺) 147

DMSO-d₆ 1.20(3H, t, J=5.4 Hz) 1.82-1.85(4H, m) 2.58-2.62(3H, m)2.96-3.04(2H, m) 3.15-3.26(2H, m) 4.11(2H, t, J=4.3 Hz) 4.16(2H, q,J=5.4 Hz) 4.69-4.75(1H, m) 7.10(2H, d, J=6.6 Hz) 7.24-7.28(1H, m)7.32-7.38(4H, m) 7.73(2H, d, J=6.6 Hz) 7.77(2H, d, J=6.3 Hz) # 7.94(2H,d, J=6.3 Hz) 8.72-8.83(2H, m) 8.88(1H, d, J=5.8 Hz) KBr 3332 2938 27231750 1630 1605 1535 1495 1204 1183 475 (free base, MH⁺) 

TABLE 77 Ex. ¹H-NMR δ (ppm), IR Elemental No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 148

DMSO-d₆ 1.16(3H, t, J=7 Hz) 1.65-1.92(4H, m) 2.53(3H, s) 2.93(2H, t, J=6Hz) 3.07(2H, t, J=6 Hz) 3.12-3.25(2H, m) 4.12(2H, t, J=7 Hz)7.19-7.33(5H, m) 7.54(1H, dd, J=3.9 Hz) 7.59(1H, d, J=9 Hz) 8.68(2H,brs) 9.08(1H, d, J=9 Hz) 12.08(1H, brs) #KBr 3343 2936 1741 1638 1550467 (free base, MH⁺) 149

DMSO-d₆ 1.14(3H, t, J=6.8 Hz) 1.66-1.82(4H, m) 2.42-2.58(6H, m)2.84-3.22(6H, m) 4.09(2H, q, J=6.8 Hz) 4.64-4.68(1H, m) 7.18-7.34(5H, m)7.98(2H, d, J=8.6 Hz) 8.08(2H, d, J=8.6 Hz) 8.68(1H, br) 9.04(1H, d,J=7.2 Hz) #KBr 3423 2938 1735 1617 1560 1211 451 (free base, MH⁺) 

TABLE 78 ¹H-NMR δ (ppm), IR Elemental Ex. No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 150

DMSO-d₆ 1.70-1.88(4H, m) 2.53(3H, m) 2.90-3.70(6H, m) 4.76(1H, m)7.20-7.28(5H, m) 7.55-7.56(2H, m) 8.04(1H, d, J=6.0 Hz) 8.62(2H, m)9.03(1H, d, J=6.0 Hz) 12.12(1H, s) 13.0(1H, brs) KBr 1735 1623 1545 1224#439 (free base, MH⁺) 151

DMSO-d₆ 1.69-1.88(4H, m) 2.34(3H, s) 2.53(3H, m) 2.89-3.80(6H, m)5.62(1H, m) 7.20-7.32(5H, m) 7.52(1H, d, J=6 Hz) 7.55(1H, s) 7.59(1H, d,J=6 Hz) 8.69(2H, brs) 9.40(1H, d, J=6.0 Hz) 12.06(1H, s) KBr 1654 15421437 1231 #477 (free base, MH⁺) 

TABLE 79 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 152

DMSO-d₆ 1.15(3H, t, J=15 Hz) 2.18(2H, m) 2.57(3H, m) 2.90-3.50(6H, m)4.12(2H, q, J=15 Hz) 4.60(1H, m) 7.21-7.34(5H, m) 7.73(1H, d, J=9 Hz)7.82(1H, d, J=9 Hz) 8.09(1H, s) 8.80(2H, brs) 8.91(1H, d, J=6 Hz) 442(free base, MH⁺) 153

DMSO-d₆ 1.11-1.83(11H, m) 2.52(3H, m) 2.83-3.57(6H, m) 4.10(2H, q, J=18Hz) 4.65(1H, m) 7.20-7.83(7H, m) 8.12(1H, s) 8.94(3H, m) KBr 1738 16431497 1469 484 (free base, MH⁺) 

TABLE 80 Ex. ¹H-NMR δ (ppm), IR FAB- Elemental No. Compound 300 MHz(cm⁻¹) MS analysis (%) 154

CDCl₃ 1.24(3H, t, J=7.3 Hz) 1.70-1.83(2H, m) 1.97-2.08(2H, m) 2.65(3H,s) 2.92-3.02(4H, m) 3.21(2H, d, J=5.8 Hz) 3.80(3H, s) 4.18(2H, q, J=7.3Hz) 5.03(1H, q, J=5.8 Hz) 6.83(1H, d, J=1.3 Hz) 6.93(1H, dd, J=8.2, 1.3Hz) 7.15-7.28(5H, m) 8.08(1H, d, J=8.2 Hz) # 8.27(1H, d, J=7.3 Hz)9.56(2H, brs) 445 (free base, MH⁺) 

TABLE 81 ¹H-NMR δ (ppm), IR Elemental Ex. No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 155

DMSO-d₆ 1.14(3H, t, J=7 Hz) 3.08-3.60(14H, m) 4.12(2H, q, J=7 Hz)7.15-7.32(5H, m) 8.31(1H, s) 9.58(1H, d, J=9 Hz) 9.59(2H, brs) KBr 34361774 1638 1459 538 (free base, MH⁺) 156

DMSO-d₆ 0.93(3H, t, J=6.0 Hz) 1.17(3H, t, J=6.0 Hz) 1.66-1.92(4H, m)2.22-2.34(2H, m) 2.78-3.36(6H, m) 4.11(2H, q, J=6.0 Hz) 4.70-4.78(1H, m)6.98(1H, s) 7.24-7.32(5H, m) 8.11(1H, s) 8.89(1H, brs) 9.08(1H, d, J=7.2Hz) 12.37(1H, s) #KBr 3342 2972 1738 1651 1262 1182 503 (free base, MH⁺) 

TABLE 82 ¹H-NMR δ (ppm), IR Elemental Ex. No. Compound 300 MHz (cm⁻¹)FAB-MS analysis (%) 157

CDCl₃ 2.20-2.34(2H, m) 2.71(3H, s) 2.77(2H, t, J=5 Hz) 3.11(2H, brs)3.23(2H, ddd, J=13, 8, 5 Hz) 3.77(3H, s) 5.01(1H, ddd, J=8, 8, 5 Hz)6.60(1H, dd, J=9, 2 Hz) 6.73(1H, d, J=2 Hz) # 6.97(1H, d, J=8 Hz)7.13(2H, dd, J=8, 2 Hz) 7.24-7.32(3H, m) 7.37(1H, d, J=9 Hz) 9.51(2H,brs) 12.12(1H, s) #415 (free base, MH⁺) 158

CDCl₃ 2.20-2.40(2H, m) 2.71-2.85(4H, m) 3.05-3.25(4H, m) 3.77(1H, s)4.9(1H, q, J=7.2 Hz) 6.86(1H, s) 7.14-7.30(6H, m) 7.67(1H, s) 9.43(2H,brs) 11.91(1H, s) 493 (free base, MH⁺) 

Formulation Examples of the pharmaceuctical agents containing thecompound of the present invention are shown in the following.

Formulation Example 1 (Tablet) (1) Compound of Example 18 10 g (2)Lactose 50 g (3) Corn starch 15 g (4) Carboxymethylcellulose sodium 44 g(5) Magnesium stearate  1 g 

The entire amounts of (1), (2) and (3), and 30 g of (4) were kneadedwith water, dried in vacuo, and granulated. The granules were added with14 g of (4) and 1 g of (5), and the mixture was compressed to givetablets, whereby 1,000 tablets containing 10 mg of the compound pertablet were prepared.

FORMULATION EXAMPLE 2

(Injection)

The compound of Example 18 (100 mg) was dissolved in an aqueous solutionof mannitol (5 g) dissolved in water (100 ml) for injection, sterilizedby filtrating through a 0.22 μm filter, and filled in sterilizedampoules by 1 ml to give injections containing 1 mg of the compound perampoule.

The results of experiments with respect to the suppression of productionof inflammatory cytokines, suppression of LPS-induced peritonitis andsuppression of LPS/D-glactosamine-induced hepatitis by the compound ofthe present invention are shown below.

EXPERIMENTAL EXAMPLE 1

Suppression of production of inflammatory cytokines

Thirty ml of human peripheral blood added with heparin was placed onFicol-Paque (15 ml), and centrifuged at 400 G for 40 minutes at roomtemperature. The obtained monocyte fraction layers were collected andwashed three times with E-MEM medium. The cells were adjusted to a finalconcentration of 0.5×10⁵ cells/800 μl with RPMI-1640 medium containing5% bovine fetal serum (2-mercaptoethanol), and seeded in a 24 well plantby 800 μl. A test sample (100 μl) was added and 100 μl oflipopolysarcharide (LPS, 100 μg/ml) was added one hour later. Thesupernatant was taken at 20 hours after stimulation with LPS, andamounts of various cytokines were determined using an ELISA kit. Byplotting the cytokine amounts at various concentrations, theconcentration of the test sample necessary for inhibition by 50% (IC₅₀)was determined. The results are shown in Tables 83-88.

TABLE 83 IC₅₀ (μM) IL-1β TNF IL-8 Example No. 1 0.002 0.008 0.009Example No. 2 — — 0.01 Example No. 3 >30 14 >30 Example No. 4 3 2 2Example No. 5 75 6 6 Example No. 6 14 6 14 Example No. 7 — — 8 ExampleNo. 9 — — <0.3 Example No. 10 — — 0.6 Example No. 11 — — 0.4 Example No.14 — — 1 Example No. 15 — — 1 Example No. 16 — — 0.03 Example No. 18 — —<0.01 Example No. 19 — — <0.01 Example No. 20 — — 29 Example No. 21 — —<0.01 Example No. 22 — — <0.01 Example No. 24 — — 0.02 Example No. 25 —— 0.01 Example No. 26 — — 0.009 

TABLE 84 IC₅₀ (μM) IL-1β TNF IL-8 Example No. 27 — — <0.01 Example No.28 — — <0.01 Example No. 29 — — <0.01 Example No. 30 — — 0.6 Example No.31 — — <0.01 Example No. 32 — — 0.5 Example No. 34 — — 2 Example No. 36— — 0.06 Example No. 37 — — 0.3 Example No. 39 — — 0.02 Example No. 40 —— 0.01 Example No. 41 — — <0.01 Example No. 42 — — 0.1 Example No. 43 —— 0.03 Example No. 44 — — <0.01 Example No. 45 0.0008 0.004 0.004Example No. 46 — — <0.01 Example No. 47 — — 3 Example No. 48 — — 0.2Example No. 49 — — 0.02 Example No. 50 — — 28 

TABLE 85 IC₅₀ (μM) IL-1β TNF IL-8 Example No. 51 — — 7 Example No. 52 —— <0.01 Example No. 53 — — <0.01 Example No. 54 — — <0.01 Example No. 55— — <0.01 Example No. 56 — — 4 Example No. 57 — — 0.05 Example No. 58 —— 0.02 Example No. 60 — — 0.03 Example No. 63 — — 0.1 Example No. 64 — —0.05 Example No. 67 — — 0.05 Example No. 68 — — 0.001 Example No. 69 — —<0.001 Example No. 70 — — 0.006 Example No. 71 — — 0.04 Example No. 72 —— 0.1 Example No. 73 — — <0.01 Example No. 74 — — 0.07 Example No. 75 —— 0.04 Example No. 76 — — 0.3 

TABLE 86 IC₅₀ (μM) IL-1β TNF IL-8 Example No. 77 — — 3 Example No. 80 —— 3 Example No. 81 — — 4 Example No. 82 — — 0.02 Example No. 83 — — 0.09Example No. 84 — — 0.03 Example No. 85 — — 0.07 Example No. 86 — —<0.001 Example No. 87 — — 0.2 Example No. 88 — — 3 Example No. 89 — —0.6 Example No. 90 — — 0.6 Example No. 91 — — 0.001 Example No. 92 — —0.03 Example No. 94 — — 1 Example No. 95 — — 0.09 Example No. 96 — —0.003 Example No. 98 — — 0.001 Example No. 99 — — 0.001 Example No. 100— — 0.001 Example No. 101 — — 0.003 

TABLE 87 IC₅₀ (μM) IL-1β TNF IL-8 Example No. 102 — — 0.002 Example No.103 — — 0.7 Example No. 104 — — 0.7 Example No. 105 0.001 0.004 0.005Example No. 106 — — <0.01 Example No. 110 — — <0.01 Example No. 111 — —<0.01 Example No. 117 — — <0.01 Example No. 122 — — <0.01 Example No.125 — — 0.01 Example No. 126 — — 0.8 Example No. 127 — — 0.2 Example No.128 — — 0.2 Example No. 129 — — 2 Example No. 132 — — 0.07 Example No.133 — — 0.2 Example No. 134 — — 0.2 Example No. 136 — — 0.2 Example No.137 — — 2 Example No. 138 — — 1 Example No. 139 — — 4 

TABLE 88 IC₅₀ (μM) IL-1β TNF IL-8 Example No. 140 — — 13 Example No. 141— — 3 Example No. 142 — — 0.4 Example No. 143 — — 3 Example No. 144 — —29 Example No. 146 — — 5 Example No. 147 — — 2 Example No. 148 — — 4Example No. 149 — — 3 Example No. 152 — — 7 Example No. 153 — — 1Example No. 155 — — 0.2 Example No. 156 — — 2 

EXPERIMENTAL EXAMPLE 2

Suppression of LPS-induced peritonitis

LPS (30 μg/ml, 1 ml) prepared with physiological saline containing 0.5%CMC (carboxymethylcellulose) was infra-peritoneally injected into maleBalb/c mice to induce-peritonitis. One hour later, the mice were killedwith carbon dioxide, and the amount of TNF α in the peritoneal fluid wasdetermined using an ELISA kit.

The test sample (50 mg/kg) was administered from the tail vein at 60minutes before LPS injection, and the degree of suppression wasinvestigated. The suppression by the test sample is shown in the ratiorelative to the suppression in the control group.

Suppression (%)=100-(TNR amount of group treated with test sample/TNFamount of control group)×100

The results are shown in Table 89 wherein ** means the presence ofsignificant difference by p<0.01 from the control group.

TABLE 89 Inhibition (%) Example No. 1 64** Example No. 4 38** ExampleNo. 9 21   Example No. 19 32** Example No. 51 38** Example No. 52 31**Example No. 148 19   Example No. 155 28** 

EXPERIMENTAL EXAMPLE 3

Suppression of LPS/D-galactosamine-induced hepatitis

LPS (5 μg/kg)D-galactosamine (500 mg/kg) in physiological saline wasintraperitoneally injected to male C57BL/6 mice to induce hepatitis. Sixhours after the injection of LPS/D-galactosamine in physiologicalsaline, blood was taken from the mice orbital venosus plexus. Plasma wasseparated from the blood, and ALT in blood was determined by abiochemical analyzer. The test sample was administered from the tailvein at 10 minutes before the injection of LPS/D-galactosamine inphysiological saline, and the degree of suppression was investigated.The suppression by the test sample is shown in the ratio relative to thesuppression in the control group.

Suppression (%)=100-(ALT amount of group treated with test sample/ALTamount of control group)×100

The result are shown in Tables 90-91.

TABLE 90 Dose (mg/kg) Inhibition (%) Example No. 1  5 88 10 78 ExampleNo. 2 10 65 Example No. 4 10 42 Example No. 10 10 77 Example No. 18 1086 Example No. 22 10 51 Example No. 24 10 63 Example No. 27 10 67Example No. 31  5 87 Example No. 32 10 78 Example No. 36 10 47 ExampleNo. 37 10 80 

TABLE 91 Dose (mg/kg) Inhibition (%) Example No. 40 10 49 Example No. 4510 30 Example No. 46 10 57 Example No. 50 10 15 Example No. 54  5 74Example No. 60 10 42 Example No. 61 10  6 Example No. 105 10 40 ExampleNo. 117 10 54 Example No. 123 10 41 Example No. 126 10 27 Example No.127  5 82 Example No. 138  5 22 

From the foregoing results, it is evident that the compound of thepresent invention suppresses production of inflammatory cytokines and isuseful for the prophylaxis and therapy of noninfectious or infectionsdiseases accompanied by neutrophile migration, which are represented byrheumatic diseases (e.g., rheumatoid arthritis); arthritis due to gout;systemic lupus erythematosus; dermatopathy (e.g., psoriasis, pustulosisand atopic dermatitis); respiratory diseases (e.g., bronchial asthma,bronchitis, ARDS and diffused interstitial pneumonia); inflammatorybowel diseases (e.g., ulcerative colitis and Crohn's disease); acute orchronic hepatitis inclusive of fulminant hepatitis; acute or chronicglomerulonephritis; nephropyelitis; uveitis caused by Behcet disease andvogt-Koyanagi Harada disease; Mediterranean fever (polyserositis);ischemic disease (e.g., myocardial infarction); and systemic circulatoryfailure and multi-organ failure caused by sepsis.

The test results with respect to inflammatory cytokines such as IL-6 andGM-CSF have confirmed suppression of these inflammatory cytokines by thecompound of the present invention.

1. An amide compound of the formula (I):

  wherein: R is a piperazinyl optionally substituted by lower alkyl, apiperidyl optionally substituted by lower alkyl or an amino whereinamino is optionally substituted by lower alkyl; A is a linear alkylene;X is an oxygen atom, a sulfur atom, —NH—or—CH₂—; M is an arylene; R¹,R², R³ and R⁴ are the same or different and each is a hydrogen atom,provided at least one of R′, R¹, R², R³ and R⁴ is not a hydrogen atom, ahydroxy, a halogen atom, or —O—CO—R¹¹″′ wherein R¹¹″′ is lower alkyloptionally substituted by a substituent selected from the groupconsisting of amino, acyloxy and benzyloxycarbonyl, or phenyl optionallysubstituted by lower alkyl; R⁵ is hydrogen atom; m is 1; R⁶ is a phenyland R⁷ is —COO—R^(12″) wherein R¹²″′ is hydrogen atom, aralkyl,adamantyl, cyclohexylideneamino, cyclohexyl optionally substituted bylower alkyl, piperidyl optionally substituted by lower alkyl, or alkyloptionally substituted by a substituent selected from the groupconsisting of hydroxy, lower alkoxy, lower alkoxy lower alkoxy, loweralkoxycarbonyl, acyloxy, piperazinyl and amino optionally substituted bylower alkyl; or a pharmaceutically acceptable acid addition saltthereof.
 2. The amide compound of claim 1, wherein H M is phenylene, ora pharmaceutically acceptable acid addition salt thereof.
 3. The amidecompound of claim 1, wherein R⁷ is —COO—R¹²″″ wherein R¹²″″ is loweralkyl, or cyclohexyl which is optionally substituted by lower alkyl, ora pharmaceutically acceptable acid addition salt thereof.
 4. The amidecompound of claim 1, wherein X is an oxygen atom or —CH₂—, or apharmaceutically acceptable acid addition salt thereof.
 5. The amidecompound of claim 1, wherein R⁶ is phenyl and m is 1, or apharmaceutically acceptable acid addition salt thereof.
 6. The amidecompound of claim 1, wherein R¹, R², R³ and R⁴ are the same or differentand each is a hydrogen atom provided that at least one of R¹, R², R³ andR⁴ is not a hydrogen atom, hydroxy, a halogen atom, or —O—CO—R¹¹″″wherein R¹¹″″ is lower alkyl or phenyl, or a pharmaceutically acceptableacid addition salt thereof.
 7. A pharmaceutical composition comprising apharmaceutically acceptable carrier; and the amide compound of any oneof claims 1 to 6 or a pharmaceutically acceptable acid addition saltthereof.
 8. A method for suppressing the production of cytokines,comprising administering to a patient in need thereof, an inflammatorycytokine production suppressor comprising an amide compound of any oneof claims 1 to 6 or a pharmaceutically acceptable acid addition saltthereof as an active ingredient.
 9. A method for treating or prophylaxisof inflammatory diseases, comprising administering to a patient in needthereof, an agent for treating or prophylaxis of inflammatory diseasescomprising an amide compound of any one of claims 1 to 6 or apharmaceutically acceptable acid addition salt thereof as an activeingredient.
 10. An amide compound of formula:

  or a pharmaceutically acceptable acid addition salt thereof.
 11. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and the amide compound of claim 10 or a pharmaceuticallyacceptabe acid addition salt thereof.
 12. A method of suppressing theproduction of cytokines, comprising administering to a patient in a needthereof, an inflammatory cytokine production suppressor comprising theamide compound of claim 10 or a pharmaceutically acceptable acidaddition salt thereof as an active ingredient.
 13. A method for treatingor prophylaxis of inflammatory diseases, comprising administering to apatient in need thereof, an agent for treating or prophylaxis ofinflammatory diseases comprising the amide compound of claim 10 or apharmaceutically acceptable acid addition salt thereof as an activeingredient.
 14. An amide compound of the formula:

 
 15. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and the amide compound of claim
 14. 16. A method ofsuppressing the production of cytokines, comprising administering to apatient in need thereof, an inflammatory cytokine production suppressorcomprising the amide compound of claim
 14. 17. A method for treating orprophylaxis of inflammatory diseases, comprising administering to apatient in need thereof, an agent for treating or prophylaxis ofinflammatory diseases comprising the amide compound of claim 14.